Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Reverse engineering Lewy bodies: how far have we come and how far can we go?

Nature Reviews Neuroscience volume 22, pages 111–131 (2021)Cite this article

Subjects

A Publisher Correction to this article was published on 02 March 2021

This article has been updated

Abstract

Lewy bodies (LBs) are α-synuclein (α-syn)-rich intracellular inclusions that are an important pathological hallmark of Parkinson disease and several other neurodegenerative diseases. Increasing evidence suggests that the aggregation of α-syn has a central role in LB formation and is one of the key processes that drive neurodegeneration and pathology progression in Parkinson disease. However, little is known about the mechanisms underlying the formation of LBs, their biochemical composition and ultrastructural properties, how they evolve and spread with disease progression, and their role in neurodegeneration. In this Review, we discuss current knowledge of α-syn pathology, including the biochemical, structural and morphological features of LBs observed in different brain regions. We also review the most used cellular and animal models of α-syn aggregation and pathology spreading in relation to the extent to which they reproduce key features of authentic LBs. Finally, we provide important insights into molecular and cellular determinants of LB formation and spreading, and highlight the critical need for more detailed and systematic characterization of α-syn pathology, at both the biochemical and structural levels. This would advance our understanding of Parkinson disease and other neurodegenerative diseases and allow the development of more-reliable disease models and novel effective therapeutic strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Histological properties and proposed staging of cortical and brainstem Lewy bodies and Lewy neurites from patients with Parkinson disease.
Fig. 2: Diversity of immunostaining patterns of cortical and brainstem Lewy bodies from patients with PD.
Fig. 3: A proposed model for the de novo formation of Lewy bodies.
Fig. 4: A model for the spreading of fibrillar α-synuclein pathology.
Fig. 5: Tools and platforms for dissecting the diversity of Lewy bodies and evaluating the α-synuclein aggregation states in cellular and animal models.

Similar content being viewed by others

Change history

References

  1. Goedert, M., Spillantini, M. G., Del Tredici, K. & Braak, H. 100 years of Lewy pathology. Nat. Rev. Neurol. 9, 13–24 (2013).

    CAS  PubMed  Google Scholar 

  2. Klein, C. & Westenberger, A. Genetics of Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2, a008888 (2012).

    PubMed  PubMed Central  Google Scholar 

  3. Bartels, T., Kim, N. C., Luth, E. S. & Selkoe, D. J. N-alpha-acetylation of α-synuclein increases its helical folding propensity, GM1 binding specificity and resistance to aggregation. PLOS ONE 9, e103727 (2014).

    PubMed  PubMed Central  Google Scholar 

  4. Binolfi, A. et al. Interaction of alpha-synuclein with divalent metal ions reveals key differences: a link between structure, binding specificity and fibrillation enhancement. J. Am. Chem. Soc. 128, 9893–9901 (2006).

    CAS  PubMed  Google Scholar 

  5. Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997). This is the first study that reports the presence of α-syn in LBs of post-mortem brain tissues of patients with PD and dementia with LBs.

    CAS  PubMed  Google Scholar 

  6. Fujiwara, H. et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160–164 (2002). This is the first study that demonstrated, using mass spectrometry and phospho-specific antibodies, that α-syn in LBs is extensively phosphorylated at S129, thus paving the way for the use of pS129 α-syn as a key marker of LBs and α-syn pathology formation.

    CAS  PubMed  Google Scholar 

  7. Anderson, J. P. et al. Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. 281, 29739–29752 (2006). This study applies unbiased biochemical and mass spectrometry-based approaches to map α-syn PTMs in LBs from patients with dementia with LBs and demonstrates that LBs were enriched with multiple modified forms of α-syn, with phosphorylation at S129 being the most dominant modification.

    CAS  PubMed  Google Scholar 

  8. Hasegawa, M. et al. Phosphorylated α-synuclein is ubiquitinated in α-synucleinopathy lesions. J. Biol. Chem. 277, 49071–49076 (2002).

    CAS  PubMed  Google Scholar 

  9. Baba, M. et al. Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am. J. Pathol. 152, 879–884 (1998). This work uses antibodies raised against purified LBs to provide direct biochemical, immunohistochemical and immunoelectron microscopic evidence for the presence of aggregated and insoluble α-syn (full-length and truncated species) in LBs from patients with PD and dementia with LBs.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Crowther, R. A., Jakes, R., Spillantini, M. G. & Goedert, M. Synthetic filaments assembled from C-terminally truncated α-synuclein. FEBS Lett. 436, 309–312 (1998).

    CAS  PubMed  Google Scholar 

  11. Giasson, B. I. et al. Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions. Science 290, 985–989 (2000).

    CAS  PubMed  Google Scholar 

  12. Li, W. et al. Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc. Natl Acad. Sci. USA 102, 2162–2167 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Moors, T. E. et al. Detailed structural orchestration of Lewy pathology in Parkinson’s disease as revealed by 3D multicolor STED microscopy. bioRxiv https://doi.org/10.1101/470476 (2018). This article examines the distribution of α-syn species and neurofilaments in nigral LBs and demonstrates concentric structural organization of LBs with truncated α-syn species dominating the core region, which is surrounded by layers of phosphorylated α-syn species and neurofilaments.

  14. Duda, J. E. et al. Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. Am. J. Pathol. 157, 1439–1445 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Öhrfelt, A. et al. Identification of novel α-synuclein isoforms in human brain tissue by using an online NanoLC-ESI-FTICR-MS method. Neurochem. Res. 36, 2029–2042 (2011).

    PubMed  PubMed Central  Google Scholar 

  16. Kellie, J. F. et al. Quantitative measurement of intact alpha-synuclein proteoforms from post-mortem control and Parkinson’s disease brain tissue by intact protein mass spectrometry. Sci. Rep. 4, 5797 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Jensen, P. H. et al. Microtubule-associated protein 1B is a component of cortical Lewy bodies and binds α-synuclein filaments. J. Biol. Chem. 275, 21500–21507 (2000).

    CAS  PubMed  Google Scholar 

  18. Ikenaka, K., Suzuki, M., Mochizuki, H. & Nagai, Y. Lipids as trans-acting effectors for α-synuclein in the pathogenesis of Parkinson’s disease. Front. Neurosci. 13, 693 (2019).

    PubMed  PubMed Central  Google Scholar 

  19. Shahmoradian, S. H. et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nat. Neurosci. 22, 1099–1109 (2019). In this study, the authors use advanced EM techniques to show that nigral LBs are composed of a complex and crowded mixture of vesicular structures, dysmorphic organelles, lipids and non-fibrillar α-syn species. Filaments of undefined composition are detected in some LB inclusions.

    CAS  PubMed  Google Scholar 

  20. Mahul-Mellier, A. L. et al. The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proc. Natl Acad. Sci. USA 117, 4971–4982 (2020). This study describes a neuronal seeding-based model that reproduces several key events leading to the formation of LBs, including seeding, fibrillization and formation of inclusions that recapitulate many of the key biochemical, morphological and organizational features of bona fide LBs.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Iwatsubo, T. et al. Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. Am. J. Pathol. 148, 1517–1529 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M. & Goedert, M. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc. Natl Acad. Sci. USA 95, 6469–6473 (1998). This study shows that α-syn filaments can be isolated from LBs and suggests that α-syn forms the major filamentous component of LBs seen in previous EM studies of LBs.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Paleologou, K. E. et al. Detection of elevated levels of soluble α-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain 132, 1093–1101 (2009).

    PubMed  Google Scholar 

  24. Roberts, R. F., Wade-Martins, R. & Alegre-Abarrategui, J. Direct visualization of α-synuclein oligomers reveals previously undetected pathology in Parkinson’s disease brain. Brain 138, 1642–1657 (2015).

    PubMed  PubMed Central  Google Scholar 

  25. Sekiya, H. et al. Wide distribution of α-synuclein oligomers in multiple system atrophy brain detected by proximity ligation. Acta Neuropathol. 137, 455–466 (2019).

    CAS  PubMed  Google Scholar 

  26. Forno, L. S. Concentric hyalin intraneuronal inclusions of Lewy type in the brains of elderly persons (50 incidental cases): relationship to parkinsonism. J. Am. Geriatr. Soc. 17, 557–575 (1969).

    CAS  PubMed  Google Scholar 

  27. Forno, L. S. & Norville, R. L. Ultrastructure of Lewy bodies in the stellate ganglion. Acta Neuropathol. 34, 183–197 (1976). This is one of the early studies that demonstrates the compositional and ultrastructural diversity of LBs and reveals that some LBs are not only composed of filamentous structures but are also enriched in vesicular structures, mitochondria, multivesicular bodies and other organelles.

    CAS  PubMed  Google Scholar 

  28. Langston, J. W. & Forno, L. S. The hypothalamus in Parkinson disease. Ann. Neurol. 3, 129–133 (1978).

    CAS  PubMed  Google Scholar 

  29. Gibb, W. R. G., Scott, T. & Lees, A. J. Neuronal inclusions of Parkinson’s disease. Mov. Disord. 6, 2–11 (1991).

    CAS  PubMed  Google Scholar 

  30. Kuusisto, E., Parkkinen, L. & Alafuzoff, I. Morphogenesis of Lewy bodies: dissimilar incorporation of α-synuclein, ubiquitin, and p62. J. Neuropathol. Exp. Neurol. 62, 1241–1253 (2003). This study presents one of the most extensive profilings of the diversity of nigral pale bodies and LBs and explores the relationship between these two types of inclusions using immunohistochemical detection of α-syn, ubiquitin and p62.

    CAS  PubMed  Google Scholar 

  31. Lewy, F. H. Paralysis agitans. I. Pathologische Anatomie.in Handbuch der Neurologie (ed. Lewandowsky, M)(1912).

  32. Duvoisin, R. C. A brief history of parkinsonism. Neurol. Clin. 10, 301–316 (1992).

    CAS  PubMed  Google Scholar 

  33. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).

    PubMed  Google Scholar 

  34. Hawkes, C. H., Del Tredici, K. & Braak, H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol. Appl. Neurobiol. 33, 599–614 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Rey, N. L., Wesson, D. W. & Brundin, P. The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases. Neurobiol. Dis. 109, 226–248 (2018).

    CAS  PubMed  Google Scholar 

  36. Atik, A., Stewart, T. & Zhang, J. Alpha-synuclein as a biomarker for Parkinson’s Disease. Brain Pathol. 26, 410–418 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Olanow, C. W., Stocchi, F., and Lang, A. Parkinson’s Disease: Non-motor and Non-dopaminergic Features (John Wiley & Sons, 2011).

  38. Beyer, K. Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol. 112, 237–251 (2006).

    CAS  PubMed  Google Scholar 

  39. Narhi, L. et al. Both familial Parkinson’s disease mutations accelerate α-synuclein aggregation. J. Biol. Chem. 274, 9843–9846 (1999).

    CAS  PubMed  Google Scholar 

  40. Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047 (1997).

    CAS  PubMed  Google Scholar 

  41. Greenbaum, E. A. et al. The E46K mutation in α-synuclein increases amyloid fibril formation. J. Biol. Chem. 280, 7800–7807 (2005).

    CAS  PubMed  Google Scholar 

  42. Kosaka, K. Lewy bodies in cerebral cortex, report of three cases. Acta Neuropathol. 42, 127–134 (1978).

    CAS  PubMed  Google Scholar 

  43. Wakabayashi, K. et al. Accumulation of α-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol. 96, 445–452 (1998). This study uses antibodies to full-length α-syn or the 42–62 domain of α-syn to demonstrate the presence of α-syn in degenerating neurites and intracytoplasmic accumulations (LBs, glial cytoplasmic inclusions, neuronal cytoplasmic inclusions and neuronal nuclear inclusions), which represent common pathological features of LB disease and multiple system atrophy.

    CAS  PubMed  Google Scholar 

  44. Beyer, K. & Ariza, A. α-Synuclein posttranslational modification and alternative splicing as a trigger for neurodegeneration. Mol. Neurobiol. 47, 509–524 (2013).

    CAS  PubMed  Google Scholar 

  45. Huang, Y. & Halliday, G. Can we clinically diagnose dementia with Lewy bodies yet? Transl. Neurodegener. 2, 4 (2013).

    PubMed  PubMed Central  Google Scholar 

  46. Irwin, D. J., Lee, V. M. & Trojanowski, J. Q. Parkinson’s disease dementia: convergence of α-synuclein, tau and amyloid-beta pathologies. Nat. Rev. Neurosci. 14, 626–636 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Fares, M. B. et al. The novel Parkinson’s disease linked mutation G51D attenuates in vitro aggregation and membrane binding of α-synuclein, and enhances its secretion and nuclear localization in cells. Hum. Mol. Genet 23, 4491–4509 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Li, B. et al. Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel. Nat. Commun. 9, 3609 (2018).

    PubMed  PubMed Central  Google Scholar 

  49. Araki, K. et al. Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein. Proc. Natl Acad. Sci. USA 116, 17963–17969 (2019). Using microbeam X-ray diffraction, this study confirms that α-syn-positive LBs in the brains of patients contain fibrils that possess the cross-β structure characteristics for amyloid fibrils.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Lowe, J. et al. Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson’s disease, Pick’s disease, and Alzheimer’s disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and Mallory bodies in alcoholic liver disease. J. Pathol. 155, 9–15 (1988).

    CAS  PubMed  Google Scholar 

  51. Kuzuhara, S., Mori, H., Izumiyama, N., Yoshimura, M. & Ihara, Y. Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol. 75, 345–353 (1988). This study shows that all LBs from brainstem and cortical brain regions are recognized by antibodies to ubiquitin and demonstrates that peripherally located filaments in LBs are ubiquitinated, thus paving the way for the use of ubiquitin as a marker of LBs.

    CAS  PubMed  Google Scholar 

  52. Ghosh, D. et al. The Parkinson’s disease-associated H50Q mutation accelerates alpha-synuclein aggregation in vitro. Biochemistry 52, 6925–6927 (2013).

    CAS  PubMed  Google Scholar 

  53. Ishii, T., Haga, S. & Tokutake, S. Presence of neurofilament protein in Alzheimer’s neurofibrillary tangles (ANT). An immunofluorescent study. Acta Neuropathol. 48, 105–112 (1979).

    CAS  PubMed  Google Scholar 

  54. Dahl, D., Selkoe, D. J., Pero, R. T. & Bignami, A. Immunostaining of neurofibrillary tangles in Alzheimer’s senile dementia with a neurofilament antiserum. J. Neurosci. 2, 113–119 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Rutherford, N. J., Moore, B. D., Golde, T. E. & Giasson, B. I. Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α-synuclein. J. Neurochem. 131, 859–867 (2014).

    CAS  PubMed  Google Scholar 

  56. Kumar, S. et al. Role of sporadic parkinson disease associated mutations A18T and A29S in enhanced α-synuclein fibrillation and cytotoxicity. ACS Chem. Neurosci. 9, 230–240 (2018).

    CAS  PubMed  Google Scholar 

  57. Goldman, J. E., Yen, S. H., Chiu, F. C. & Peress, N. S. Lewy bodies of Parkinson’s disease contain neurofilament antigens. Science 221, 1082–1084 (1983).

    CAS  PubMed  Google Scholar 

  58. Duffy, P. E. & Tennyson, V. M. Phase and electron microscopic observations of Lewy bodies and melanin granules in the substantia nigra and locus caeruleus in Parkinson’s disease. J. Neuropathol. Exp. Neurol. 24, 398–414 (1965). This study presents the first ultrastructural characterization of LBs from the substantia nigra and locus coeruleus, revealing their composition and the presence of radiating filamentous structures from a dense central core, and lipofuscin positivity suggesting the presence of neuromelanin granules and lipid–protein complexes.

    Google Scholar 

  59. Forno, L. S. Neuropathology of Parkinson’s disease. J. Neuropathol. Exp. Neurol. 55, 259–272 (1996).

    CAS  PubMed  Google Scholar 

  60. Ikeda, K., Hori, A. & Bode, G. Progressive dementia with “diffuse Lewy-type inclusions” in cerebral cortex. A case report. Arch. Psychiatr. Nervenkr 228, 243–248 (1980).

    CAS  PubMed  Google Scholar 

  61. Yagishita, S., Itoh, Y., Amano, N. & Nakano, T. Atypical senile dementia with widespread Lewy type inclusion in the cerebral cortex. Acta Neuropathol. 49, 187–191 (1980).

    CAS  PubMed  Google Scholar 

  62. Tomonaga, M. Neurofibrillary tangles and Lewy bodies in the locus ceruleus neurons of the aged brain. Acta Neuropathol. 53, 165–168 (1981).

    CAS  PubMed  Google Scholar 

  63. Watanabe, I., Vachal, E. & Tomita, T. Dense core vesicles around the Lewy body in incidental Parkinson’s disease: an electron microscopic study. Acta Neuropathol. 39, 173–175 (1977).

    CAS  PubMed  Google Scholar 

  64. Uéda, K. et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 11282–11286 (1993).

    PubMed  PubMed Central  Google Scholar 

  65. Culvenor, J. G. et al. Non-Aβ component of Alzheimer’s disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Aβ amyloid. Am. J. Pathol. 155, 1173–1181 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kahle, P. J. et al. Selective insolubility of α-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am. J. Pathol. 159, 2215–2225 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Kuusisto, E., Suuronen, T. & Salminen, A. Ubiquitin-binding protein p62 expression is induced during apoptosis and proteasomal inhibition in neuronal cells. Biochem. Biophys. Res. Commun. 280, 223–228 (2001).

    CAS  PubMed  Google Scholar 

  68. Monzio Compagnoni, G. & Di Fonzo, A. Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives. Acta Neuropathol. Commun. 7, 113 (2019).

    PubMed  PubMed Central  Google Scholar 

  69. Irizarry, M. C. et al. Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson’s disease and cortical Lewy body disease contain α-synuclein immunoreactivity. J. Neuropathol. Exp. Neurol. 57, 334–337 (1998).

    CAS  PubMed  Google Scholar 

  70. Masliah, E. et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265–1269 (2000).

    CAS  PubMed  Google Scholar 

  71. Dustin, P. & Brion, J. P. [Pathology of the cytoskeleton]. Ann. Pathol. 8, 3–19 (1988).

    CAS  PubMed  Google Scholar 

  72. Leverenz, J. B. et al. Proteomic identification of novel proteins in cortical Lewy bodies. Brain Pathol. 17, 139–145 (2007). This is one of the first studies that sought to define the proteome of LBs by performing a proteomics investigation on 2,500 cortical LBs isolated by laser capture microdissection.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Basso, M. et al. Proteome analysis of human substantia nigra in Parkinson’s disease. Proteomics 4, 3943–3952 (2004).

    CAS  PubMed  Google Scholar 

  74. Werner, C. J., Heyny-von Haussen, R., Mall, G. & Wolf, S. Proteome analysis of human substantia nigra in Parkinson’s disease. Proteome Sci. 6, 8 (2008).

    PubMed  PubMed Central  Google Scholar 

  75. Kitsou, E. et al. Identification of proteins in human substantia nigra. Proteom. Clin. Appl. 2, 776–782 (2008).

    CAS  Google Scholar 

  76. Licker, V. et al. Proteomic analysis of human substantia nigra identifies novel candidates involved in Parkinson’s disease pathogenesis. Proteomics 14, 784–794 (2014).

    CAS  PubMed  Google Scholar 

  77. van Dijk, K. D. et al. The proteome of the locus ceruleus in Parkinson’s disease: relevance to pathogenesis. Brain Pathol. 22, 485–498 (2012).

    PubMed  Google Scholar 

  78. Bereczki, E. et al. Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brain 141, 582–595 (2018).

    PubMed  PubMed Central  Google Scholar 

  79. den Jager, W. A. Sphingomyelin in Lewy inclusion bodies in Parkinson’s disease. Arch. Neurol. 21, 615–619 (1969). This is the first report that describes the presence of phospholipids (for example, sphingomyelin) in LBs from the substantia nigra and locus coeruleus.

    Google Scholar 

  80. Issidorides, M. R., Mytilineou, C., Panayotacopoulou, M. T. & Yahr, M. D. Lewy bodies in parkinsonism share components with intraneuronal protein bodies of normal brains. J. Neural Transm. Park. Dis. Dement. Sect. 3, 49–61 (1991).

    CAS  PubMed  Google Scholar 

  81. Gai, W. P. et al. In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies. Exp. Neurol. 166, 324–333 (2000). In this study, the authors investigate the distribution of α-syn, ubiquitin and lipids within LBs, and their findings reveal that LBs are rich in lipids and are heterogeneous in their composition and organization.

    CAS  PubMed  Google Scholar 

  82. Araki, K. et al. Synchrotron FTIR micro-spectroscopy for structural analysis of Lewy bodies in the brain of Parkinson’s disease patients. Sci. Rep. 5, 17625 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Shahmoradian, S. H. et al. Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley. bioRxiv https://doi.org/10.1101/137976 (2017).

    Article  Google Scholar 

  84. Lashuel, H. A. Do Lewy bodies contain alpha-synuclein fibrils? and does it matter? A brief history and critical analysis of recent reports. Neurobiol. Dis. 141, 104876 (2020). This review provides a critical analysis of the findings and conclusions presented in the article by Shahmoradian et al. (2019), which argues that LBs contain non-fibrillar rather than fibrillar forms of α-syn.

    CAS  PubMed  Google Scholar 

  85. Greffard, S. et al. A stable proportion of Lewy body bearing neurons in the substantia nigra suggests a model in which the Lewy body causes neuronal death. Neurobiol. Aging 31, 99–103 (2010).

    CAS  PubMed  Google Scholar 

  86. Singleton, A. B. et al. α-Synuclein locus triplication causes Parkinson’s disease. Science 302, 841 (2003). This is the first study demonstrating that SNCA gene triplication can also cause familial PD.

    CAS  PubMed  Google Scholar 

  87. Chartier-Harlin, M.-C. et al. α-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364, 1167–1169 (2004).

    CAS  PubMed  Google Scholar 

  88. Zarranz, J. J. et al. The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55, 164–173 (2004).

    CAS  PubMed  Google Scholar 

  89. Kruger, R. et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat. Genet. 18, 106–108 (1998).

    CAS  PubMed  Google Scholar 

  90. Appel-Cresswell, S. et al. α-synuclein p.H50Q, a novel pathogenic mutation for Parkinson’s disease. Mov. Disord. 28, 811–813 (2013).

    CAS  PubMed  Google Scholar 

  91. Kiely, A. P. et al. α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy? Acta Neuropathol. 125, 753–769 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Lesage, S. et al. G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann. Neurol. 73, 459–471 (2013).

    CAS  PubMed  Google Scholar 

  93. Khalaf, O. et al. The H50Q mutation enhances α-synuclein aggregation, secretion, and toxicity. J. Biol. Chem. 289, 21856–21876 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. McLean, P. J., Kawamata, H. & Hyman, B. T. α-synuclein-enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons. Neuroscience 104, 901–912 (2001).

    CAS  PubMed  Google Scholar 

  95. Petrucelli, L. et al. Parkin protects against the toxicity associated with mutant α-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36, 1007–1019 (2002).

    CAS  PubMed  Google Scholar 

  96. Tabrizi, S. J. et al. Expression of mutant α-synuclein causes increased susceptibility to dopamine toxicity. Hum. Mol. Genet. 9, 2683–2689 (2000).

    CAS  PubMed  Google Scholar 

  97. Tofaris, G. K., Layfield, R. & Spillantini, M. G. α-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett. 509, 22–26 (2001).

    CAS  PubMed  Google Scholar 

  98. Welander, H. et al. Gelsolin co-occurs with Lewy bodies in vivo and accelerates α-synuclein aggregation in vitro. Biochem. Biophys. Res. Commun. 412, 32–38 (2011).

    CAS  PubMed  Google Scholar 

  99. Pranke, I. M. et al. α-Synuclein and ALPS motifs are membrane curvature sensors whose contrasting chemistry mediates selective vesicle binding. J. Cell Biol. 194, 89–103 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Outeiro, T. F. & Lindquist, S. Yeast cells provide insight into α-synuclein biology and pathobiology. Science 302, 1772–1775 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Gitler, A. D. et al. The Parkinson’s disease protein α-synuclein disrupts cellular Rab homeostasis. Proc. Natl Acad. Sci. USA 105, 145–150 (2008).

    CAS  PubMed  Google Scholar 

  102. Soper, J. H., Kehm, V., Burd, C. G., Bankaitis, V. A. & Lee, V. M. Aggregation of α-synuclein in S. cerevisiae is associated with defects in endosomal trafficking and phospholipid biosynthesis. J. Mol. Neurosci. 43, 391–405 (2011).

    CAS  PubMed  Google Scholar 

  103. Roberti, M. J., Bertoncini, C. W., Klement, R., Jares-Erijman, E. A. & Jovin, T. M. Fluorescence imaging of amyloid formation in living cells by a functional, tetracysteine-tagged α-synuclein. Nat. Methods 4, 345–351 (2007).

    CAS  PubMed  Google Scholar 

  104. Wakabayashi, K. et al. Synphilin-1 is present in Lewy bodies in Parkinson’s disease. Ann. Neurol. 47, 521–523 (2000).

    CAS  PubMed  Google Scholar 

  105. Xie, Y. Y. et al. Interaction with synphilin-1 promotes inclusion formation of α-synuclein: mechanistic insights and pathological implication. FASEB J. 24, 196–205 (2010).

    PubMed  Google Scholar 

  106. Engelender, S. et al. Synphilin-1 associates with α-synuclein and promotes the formation of cytosolic inclusions. Nat. Genet. 22, 110–114 (1999).

    CAS  PubMed  Google Scholar 

  107. Tanaka, M. et al. Aggresomes formed by α-synuclein and synphilin-1 are cytoprotective. J. Biol. Chem. 279, 4625–4631 (2004).

    CAS  PubMed  Google Scholar 

  108. Eyal, A. & Engelender, S. Synphilin isoforms and the search for a cellular model of Lewy body formation in Parkinson’s disease. Cell Cycle 5, 2082–2086 (2006).

    CAS  PubMed  Google Scholar 

  109. Smith, W. W. et al. α-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J. Neurosci. 25, 5544–5552 (2005). In this study, Smith et al. report that the co-expression of α-syn and synphilin 1 causes the formation of inclusion bodies that are positive for pS129 α-syn, ubiquitin and ThS and that these inclusions are composed of disorganized filaments.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Buttner, S. et al. Synphilin-1 enhances α-synuclein aggregation in yeast and contributes to cellular stress and cell death in a Sir2-dependent manner. PLoS ONE 5, e13700 (2010).

    PubMed  PubMed Central  Google Scholar 

  111. Lee, G. et al. Casein kinase II-mediated phosphorylation regulates α-synuclein/synphilin-1 interaction and inclusion body formation. J. Biol. Chem. 279, 6834–6839 (2004).

    CAS  PubMed  Google Scholar 

  112. O’Farrell, C. et al. Transfected synphilin-1 forms cytoplasmic inclusions in HEK293 cells. Brain Res. Mol. Brain Res. 97, 94–102 (2001).

    PubMed  Google Scholar 

  113. Fares, M. B. et al. Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson’s disease. Proc. Natl Acad. Sci. USA 113, E912–E921 (2016). This study demonstrates that the lack of human α-syn fibrillization in rodent neuronal models could be due to interactions between human α-syn and the endogenously expressed mouse α-syn homologue, and shows that transient expression of human WT α-syn in Snca-knockout neurons leads to the formation of spheroid fibrillar inclusions that are insoluble, ThS positive and immunoreactive for antibodies to ubiquitin and pS129 α-syn.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Proukakis, C. et al. A novel α-synuclein missense mutation in Parkinson disease. Neurology 80, 1062–1064 (2013).

    PubMed  PubMed Central  Google Scholar 

  115. Hoffman-Zacharska, D. et al. Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson’s disease. Parkinsonism Relat. Disord. 19, 1057–1060 (2013).

    PubMed  PubMed Central  Google Scholar 

  116. Pasanen, P. et al. Novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s disease-type pathology. Neurobiol. Aging 35, 2180.e1–2180.e5 (2014).

    CAS  Google Scholar 

  117. Farrer, M. et al. Comparison of kindreds with parkinsonism and α-synuclein genomic multiplications. Ann. Neurol. 55, 174–179 (2004).

    CAS  PubMed  Google Scholar 

  118. Ibáñez, P. et al. Causal relation between α-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364, 1169–1171 (2004).

    PubMed  Google Scholar 

  119. Soldner, F. et al. Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 146, 318–331 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Chung, C. Y. et al. Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science 342, 983–987 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Ryan, Scott D. et al. Isogenic human iPSC Parkinson’s model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell 155, 1351–1364 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Dettmer, U. et al. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat. Commun. 6, 7314 (2015).

    PubMed  Google Scholar 

  123. Kouroupi, G. et al. Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson’s disease. Proc. Natl Acad. Sci. USA 114, E3679–E3688 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Devine, M. J. et al. Parkinson’s disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nat. Commun. 2, 440 (2011).

    PubMed  Google Scholar 

  125. Byers, B. et al. SNCA triplication Parkinson’s patient’s iPSC-derived DA neurons accumulate α-synuclein and are susceptible to oxidative stress. PLoS ONE 6, e26159 (2011).

    PubMed  PubMed Central  Google Scholar 

  126. Flierl, A. et al. Higher vulnerability and stress sensitivity of neuronal precursor cells carrying an α-synuclein gene triplication. PLoS ONE 9, e112413 (2014).

    PubMed  PubMed Central  Google Scholar 

  127. Oliveira, L. M. et al. Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson’s patient-derived induced pluripotent stem cells. Cell Death Dis. 6, e1994 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Lin, L. et al. Molecular features underlying neurodegeneration identified through in vitro modeling of genetically diverse Parkinson’s disease patients. Cell Rep. 15, 2411–2426 (2016).

    CAS  PubMed  Google Scholar 

  129. Deas, E. et al. α-Synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson’s disease. Antioxid. Redox Signal. 24, 376–391 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Zambon, F. et al. Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson’s iPSC-derived dopamine neurons. Hum. Mol. Genet. 28, 2001–2013 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Feany, M. B. & Bender, W. W. A Drosophila model of Parkinson’s disease. Nature 404, 394–398 (2000). In this report, A30P α-syn overexpression in Drosophila leads to the formation of LB-like inclusions that exhibit some of the features of the classical brainstem LBs, including a dense core with peripherally radiating filaments.

    CAS  PubMed  Google Scholar 

  132. Mizuno, H., Fujikake, N., Wada, K. & Nagai, Y. α-Synuclein transgenic drosophila as a model of Parkinson’s disease and related synucleinopathies. Parkinsons Dis. 2011, 212706 (2010).

    PubMed  PubMed Central  Google Scholar 

  133. Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M. & Bonini, N. M. Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295, 865–868 (2002).

    CAS  PubMed  Google Scholar 

  134. Takahashi, M. et al. Phosphorylation of alpha-synuclein characteristic of synucleinopathy lesions is recapitulated in α-synuclein transgenic Drosophila. Neurosci. Lett. 336, 155–158 (2003).

    CAS  PubMed  Google Scholar 

  135. Chen, L. & Feany, M. B. α-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat. Neurosci. 8, 657–663 (2005).

    CAS  PubMed  Google Scholar 

  136. Chen, L. et al. Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J. Clin. Invest. 119, 3257–3265 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Ordonez, D. G., Lee, M. K. & Feany, M. B. α-synuclein induces mitochondrial dysfunction through spectrin and the actin cytoskeleton. Neuron 97, 108–124.e6 (2018).

    CAS  PubMed  Google Scholar 

  138. Kuwahara, T. et al. Familial Parkinson mutant α-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans. J. Biol. Chem. 281, 334–340 (2006).

    CAS  PubMed  Google Scholar 

  139. Lakso, M. et al. Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human α-synuclein. J. Neurochem. 86, 165–172 (2003).

    CAS  PubMed  Google Scholar 

  140. van Ham, T. J. et al. C. elegans model identifies genetic modifiers of α-synuclein inclusion formation during aging. PLoS Genet. 4, e1000027 (2008).

    PubMed  PubMed Central  Google Scholar 

  141. Beal, M. F. Experimental models of Parkinson’s disease. Nat. Rev. Neurosci. 2, 325–334 (2001).

    CAS  PubMed  Google Scholar 

  142. Kahle, P. J. α-Synucleinopathy models and human neuropathology: similarities and differences. Acta Neuropathol. 115, 87–95 (2008).

    CAS  PubMed  Google Scholar 

  143. Kahle, P. J. et al. Subcellular localization of wild-type and Parkinson’s disease-associated mutant α-synuclein in human and transgenic mouse brain. J. Neurosci. 20, 6365–6373 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Rockenstein, E. et al. Differential neuropathological alterations in transgenic mice expressing α-synuclein from the platelet-derived growth factor and Thy-1 promoters. J. Neurosci. Res. 68, 568–578 (2002).

    CAS  PubMed  Google Scholar 

  145. van der Putten, H. et al. Neuropathology in mice expressing human α-synuclein. J. Neurosci. 20, 6021–6029 (2000).

    PubMed  PubMed Central  Google Scholar 

  146. Chandra, S., Gallardo, G., Fernandez-Chacon, R., Schluter, O. M. & Sudhof, T. C. α-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123, 383–396 (2005).

    CAS  PubMed  Google Scholar 

  147. Rothman, S. M. et al. Neuronal expression of familial Parkinson’s disease A53T α-synuclein causes early motor impairment, reduced anxiety and potential sleep disturbances in mice. J. Parkinsons Dis. 3, 215–229 (2013).

    CAS  PubMed  Google Scholar 

  148. Neumann, M. et al. Misfolded proteinase K-resistant hyperphosphorylated α-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies. J. Clin. Invest. 110, 1429–1439 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Emmer, K. L., Waxman, E. A., Covy, J. P. & Giasson, B. I. E46K human α-synuclein transgenic mice develop Lewy-like and tau pathology associated with age-dependent, detrimental motor impairment. J. Biol. Chem. 286, 35104–35118 (2011). This study describes an α-syn transgenic mouse model (expressing E46K human α-syn) that develops motor impairments and age-dependent intracytoplasmic inclusions that recapitulate some of the biochemical, histological, and morphological features of human LBs, including the accumulation of detergent-insoluble and phosphorylated α-syn fibrils and the presence of trapped membranous organelles (for example, mitochondria).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Giasson, B. I. et al. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34, 521–533 (2002). This is one of the first α-syn transgenic mouse models (overexpressing A53T human α-syn), which develops age-dependent α-syn inclusions in the spinal cord that comprise fibrillar α-syn (10–16 nm) and are reminiscent of human cortical LBs and LNs in synucleinopathies.

    CAS  PubMed  Google Scholar 

  151. Nuber, S. et al. A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats. Brain 136, 412–432 (2013).

    PubMed  PubMed Central  Google Scholar 

  152. Cannon, J. R. et al. Expression of human E46K-mutated α-synuclein in BAC-transgenic rats replicates early-stage Parkinson’s disease features and enhances vulnerability to mitochondrial impairment. Exp. Neurol. 240, 44–56 (2013).

    CAS  PubMed  Google Scholar 

  153. Kuo, Y. M. et al. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes. Hum. Mol. Genet. 19, 1633–1650 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Matsuoka, Y. et al. Lack of nigral pathology in transgenic mice expressing human α-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol. Dis. 8, 535–539 (2001).

    CAS  PubMed  Google Scholar 

  155. Richfield, E. K. et al. Behavioral and neurochemical effects of wild-type and mutated human α-synuclein in transgenic mice. Exp. Neurol. 175, 35–48 (2002).

    CAS  PubMed  Google Scholar 

  156. Rathke-Hartlieb, S. et al. Sensitivity to MPTP is not increased in Parkinson’s disease-associated mutant α-synuclein transgenic mice. J. Neurochem. 77, 1181–1184 (2001).

    CAS  PubMed  Google Scholar 

  157. Thiruchelvam, M. J., Powers, J. M., Cory-Slechta, D. A. & Richfield, E. K. Risk factors for dopaminergic neuron loss in human α-synuclein transgenic mice. Eur. J. Neurosci. 19, 845–854 (2004).

    CAS  PubMed  Google Scholar 

  158. Wakamatsu, M. et al. Accumulation of phosphorylated α-synuclein in dopaminergic neurons of transgenic mice that express human α-synuclein. J. Neurosci. Res. 85, 1819–1825 (2007).

    CAS  PubMed  Google Scholar 

  159. Wakamatsu, M. et al. Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice. Neurobiol. Aging 29, 574–585 (2008).

    CAS  PubMed  Google Scholar 

  160. Wegrzynowicz, M. et al. Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model. Acta Neuropathol. 138, 575–595 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Klein, R. L., King, M. A., Hamby, M. E. & Meyer, E. M. Dopaminergic cell loss induced by human A30P α-synuclein gene transfer to the rat substantia nigra. Hum. Gene Ther. 13, 605–612 (2002).

    CAS  PubMed  Google Scholar 

  162. Kirik, D. et al. Parkinson-like neurodegeneration induced by targeted overexpression of α-synuclein in the nigrostriatal system. J. Neurosci. 22, 2780–2791 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Lo Bianco, C., Ridet, J. L., Schneider, B. L., Deglon, N. & Aebischer, P. α-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc. Natl Acad. Sci. USA 99, 10813–10818 (2002). This study reports a lentiviral α-syn overexpression-based model of PD that exhibits selective loss of nigral dopaminergic neurons and the appearance of human α-syn non-fibrillar positive inclusions and neuritic pathology. Similar inclusions are formed by rat α-syn in the absence of neuronal loss.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Yamada, M., Iwatsubo, T., Mizuno, Y. & Mochizuki, H. Overexpression of α-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of α-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson’s disease. J. Neurochem. 91, 451–461 (2004).

    CAS  PubMed  Google Scholar 

  165. Decressac, M., Mattsson, B., Lundblad, M., Weikop, P. & Bjorklund, A. Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons. Neurobiol. Dis. 45, 939–953 (2012).

    CAS  PubMed  Google Scholar 

  166. Azeredo da Silveira, S. et al. Phosphorylation does not prompt, nor prevent, the formation of α-synuclein toxic species in a rat model of Parkinson’s disease. Hum. Mol. Genet. 18, 872–887 (2009). This study demonstrates that AAV-mediated expression of S129A α-syn in rat SNc induces abundant expression of ThS-positive, proteinase K-resistant aggregates, which are electron dense with occasional filamentous structures.

    CAS  PubMed  Google Scholar 

  167. Paleologou, K. E. et al. Phosphorylation at S87 is enhanced in synucleinopathies, inhibits α-synuclein oligomerization, and influences synuclein-membrane interactions. J. Neurosci. 30, 3184–3198 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Kirik, D. et al. Nigrostriatal α-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein: a new primate model of Parkinson’s disease. Proc. Natl Acad. Sci. USA 100, 2884–2889 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Eslamboli, A. et al. Long-term consequences of human α-synuclein overexpression in the primate ventral midbrain. Brain 130, 799–815 (2007).

    PubMed  Google Scholar 

  170. Oliveras-Salva, M. et al. rAAV2/7 vector-mediated overexpression of α-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. Mol. Neurodegener. 8, 44 (2013).

    PubMed  PubMed Central  Google Scholar 

  171. Lauwers, E. et al. Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of alpha-synuclein. Brain Pathol. 13, 364–372 (2003).

    CAS  PubMed  Google Scholar 

  172. Cao, S., Theodore, S. & Standaert, D. G. Fcgamma receptors are required for NF-kappaB signaling, microglial activation and dopaminergic neurodegeneration in an AAV-synuclein mouse model of Parkinson’s disease. Mol. Neurodegener. 5, 42 (2010).

    PubMed  PubMed Central  Google Scholar 

  173. Lundblad, M., Decressac, M., Mattsson, B. & Bjorklund, A. Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons. Proc. Natl Acad. Sci. USA 109, 3213–3219 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. St Martin, J. L. et al. Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. J. Neurochem. 100, 1449–1457 (2007).

    Google Scholar 

  175. McNaught, K. S., Belizaire, R., Isacson, O., Jenner, P. & Olanow, C. W. Altered proteasomal function in sporadic Parkinson’s disease. Exp. Neurol. 179, 38–46 (2003).

    CAS  PubMed  Google Scholar 

  176. Rideout, H. J. & Stefanis, L. Proteasomal inhibition-induced inclusion formation and death in cortical neurons require transcription and ubiquitination. Mol. Cell Neurosci. 21, 223–238 (2002).

    CAS  PubMed  Google Scholar 

  177. Rideout, H. J., Larsen, K. E., Sulzer, D. & Stefanis, L. Proteasomal inhibition leads to formation of ubiquitin/α-synuclein-immunoreactive inclusions in PC12 cells. J. Neurochem. 78, 899–908 (2001).

    CAS  PubMed  Google Scholar 

  178. McNaught, K. S. et al. Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J. Neurochem. 81, 301–306 (2002).

    CAS  PubMed  Google Scholar 

  179. Rideout, H. J., Dietrich, P., Wang, Q., Dauer, W. T. & Stefanis, L. α-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons. J. Biol. Chem. 279, 46915–46920 (2004).

    CAS  PubMed  Google Scholar 

  180. Paxinou, E. et al. Induction of α-synuclein aggregation by intracellular nitrative insult. J. Neurosci. 21, 8053–8061 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Bedford, L. et al. Depletion of 26 S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J. Neurosci. 28, 8189–8198 (2008). This study reports that 26S proteasomal dysfunction in conditional knockout mice is sufficient to trigger neurodegeneration and fibrillar or granular inclusions that are positive for ubiquitin, ThS and p62, and contain mitochondria and/or membranous vesicles in their periphery.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Sherer, T. B. et al. An in vitro model of Parkinson’s disease: linking mitochondrial impairment to altered α-synuclein metabolism and oxidative damage. J. Neurosci. 22, 7006–7015 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Ostrerova-Golts, N. et al. The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. J. Neurosci. 20, 6048–6054 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Kakimura, J. et al. Release and aggregation of cytochrome c and α-synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole. Eur. J. Pharmacol. 417, 59–67 (2001).

    CAS  PubMed  Google Scholar 

  185. Lee, H. J., Shin, S. Y., Choi, C., Lee, Y. H. & Lee, S. J. Formation and removal of α-synuclein aggregates in cells exposed to mitochondrial inhibitors. J. Biol. Chem. 277, 5411–5417 (2002).

    CAS  PubMed  Google Scholar 

  186. Erskine, D. et al. Lewy body pathology is more prevalent in older individuals with mitochondrial disease than controls. Acta Neuropathol. 139, 219–221 (2020).

    CAS  PubMed  Google Scholar 

  187. Langston, J. W., Ballard, P., Tetrud, J. W. & Irwin, I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979–980 (1983).

    CAS  PubMed  Google Scholar 

  188. Langston, J. W. et al. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann. Neurol. 46, 598–605 (1999).

    CAS  PubMed  Google Scholar 

  189. Giraldez-Perez, R., Antolin-Vallespin, M., Munoz, M. & Sanchez-Capelo, A. Models of α-synuclein aggregation in Parkinson’s disease. Acta Neuropathol. Commun. 2, 176 (2014).

    PubMed  PubMed Central  Google Scholar 

  190. Fornai, F. et al. Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc. Natl Acad. Sci. USA 102, 3413–3418 (2005). This study demonstrates that continuous low-dose administration of MPTP produces progressive behavioural changes, causes α-syn-dependent inhibition of the ubiquitin–proteasome system and results in the formation of inclusions immunoreactive for ubiquitin and α-syn.

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Gibrat, C. et al. Differences between subacute and chronic MPTP mice models: investigation of dopaminergic neuronal degeneration and α-synuclein inclusions. J. Neurochem. 109, 1469–1482 (2009).

    CAS  PubMed  Google Scholar 

  192. Meredith, G. E. et al. Lysosomal malfunction accompanies α-synuclein aggregation in a progressive mouse model of Parkinson’s disease. Brain Res. 956, 156–165 (2002).

    CAS  PubMed  Google Scholar 

  193. Meredith, G. E., Totterdell, S., Potashkin, J. A. & Surmeier, D. J. Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol. Parkinsonism Relat. Disord. 14, S112–S115 (2008).

    PubMed  PubMed Central  Google Scholar 

  194. Shimoji, M., Zhang, L., Mandir, A. S., Dawson, V. L. & Dawson, T. M. Absence of inclusion body formation in the MPTP mouse model of Parkinson’s disease. Brain Res. Mol. Brain Res 134, 103–108 (2005).

    CAS  PubMed  Google Scholar 

  195. Alvarez-Fischer, D. et al. Modelling Parkinson-like neurodegeneration via osmotic minipump delivery of MPTP and probenecid. J. Neurochem. 107, 701–711 (2008).

    CAS  PubMed  Google Scholar 

  196. Forno, L. S., DeLanney, L. E., Irwin, I. & Langston, J. W. Similarities and differences between MPTP-induced parkinsonsim and Parkinson’s disease. Neuropathologic considerations. Adv. Neurol. 60, 600–608 (1993). This study compares neuropathological features between the MPTP-treated squirrel monkey model of PD and human PD pathology and describes similarities in neurodegeneration of the selected population of neurons and different morphologies of inclusions.

    CAS  PubMed  Google Scholar 

  197. Kowall, N. W. et al. MPTP induces α-synuclein aggregation in the substantia nigra of baboons. Neuroreport 11, 211–213 (2000).

    CAS  PubMed  Google Scholar 

  198. McCormack, A. L. et al. Pathologic modifications of α-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated squirrel monkeys. J. Neuropathol. Exp. Neurol. 67, 793–802 (2008).

    PubMed  Google Scholar 

  199. Halliday, G. et al. No Lewy pathology in monkeys with over 10 years of severe MPTP Parkinsonism. Mov. Disord. 24, 1519–1523 (2009). In this study, the authors demonstrate that MPTP administration in monkeys induces the accumulation of α-syn, but is not sufficient to trigger the formation of classical LBs.

    PubMed  Google Scholar 

  200. Fong, C. S. et al. Pesticide exposure on southwestern Taiwanese with MnSOD and NQO1 polymorphisms is associated with increased risk of Parkinson’s disease. Clin. Chim. Acta 378, 136–141 (2007).

    CAS  PubMed  Google Scholar 

  201. Liou, H. H. et al. Environmental risk factors and Parkinson’s disease: a case-control study in Taiwan. Neurology 48, 1583–1588 (1997).

    CAS  PubMed  Google Scholar 

  202. Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci. 3, 1301–1306 (2000). This study demonstrates that long-term inhibition of complex I by rotenone causes selective nigral dopaminergic cell loss, and PD-like behavioural (hypokinesia and rigidity) and neuropathological features, including the formation of α-syn and ubiquitin-positive inclusions with a dense core and radiating filaments, reminiscent of LBs.

    CAS  PubMed  Google Scholar 

  203. Sherer, T. B., Kim, J. H., Betarbet, R. & Greenamyre, J. T. Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and α-synuclein aggregation. Exp. Neurol. 179, 9–16 (2003).

    CAS  PubMed  Google Scholar 

  204. McNaught, K. S., Perl, D. P., Brownell, A. L. & Olanow, C. W. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann. Neurol. 56, 149–162 (2004).

    CAS  PubMed  Google Scholar 

  205. Vernon, A. C., Johansson, S. M. & Modo, M. M. Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson’s disease. BMC Neurosci. 11, 1 (2010).

    PubMed  PubMed Central  Google Scholar 

  206. Bezard, E., Yue, Z., Kirik, D. & Spillantini, M. G. Animal models of Parkinson’s disease: limits and relevance to neuroprotection studies. Mov. Disord. 28, 61–70 (2013).

    CAS  PubMed  Google Scholar 

  207. Wakabayashi, K., Tanji, K., Mori, F. & Takahashi, H. The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of α-synuclein aggregates. Neuropathology 27, 494–506 (2007).

    PubMed  Google Scholar 

  208. Katsuse, O., Iseki, E., Marui, W. & Kosaka, K. Developmental stages of cortical Lewy bodies and their relation to axonal transport blockage in brains of patients with dementia with Lewy bodies. J. Neurol. Sci. 211, 29–35 (2003).

    CAS  PubMed  Google Scholar 

  209. Kanazawa, T. et al. Three-layered structure shared between Lewy bodies and Lewy neurites-three-dimensional reconstruction of triple-labeled sections. Brain Pathol. 18, 415–422 (2008). In this study, the authors use three-dimensional confocal image reconstruction of serial tissue sections that were triply immunolabelled with antibodies to α-syn, ubiquitin and neurofilaments to reveal the internal three-layered structure of LBs and LNs, and provide evidence in support of the hypothesis that LNs and LBs are related and possibly formed by similar mechanisms.

    PubMed  PubMed Central  Google Scholar 

  210. Iwai, A. et al. The precursor protein of non-Aβ component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14, 467–475 (1995).

    CAS  PubMed  Google Scholar 

  211. Jakes, R., Spillantini, M. G. & Goedert, M. Identification of two distinct synucleins from human brain. FEBS Lett. 345, 27–32 (1994).

    CAS  PubMed  Google Scholar 

  212. Withers, G. S., George, J. M., Banker, G. A. & Clayton, D. F. Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Brain Res. Dev. Brain Res 99, 87–94 (1997).

    CAS  PubMed  Google Scholar 

  213. Maraganore, D. M. et al. Collaborative analysis of α-synuclein gene promoter variability and Parkinson disease. JAMA 296, 661–670 (2006).

    CAS  PubMed  Google Scholar 

  214. Farrer, M. et al. α-Synuclein gene haplotypes are associated with Parkinson’s disease. Hum. Mol. Genet. 10, 1847–1851 (2001).

    CAS  PubMed  Google Scholar 

  215. Satake, W. et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat. Genet. 41, 1303–1307 (2009).

    CAS  PubMed  Google Scholar 

  216. Simon-Sanchez, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat. Genet. 41, 1308–1312 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Ray, S. et al. α-Synuclein aggregation nucleates through liquid-liquid phase separation. Nat. Chem. 12, 705–716 (2020).

    CAS  PubMed  Google Scholar 

  218. Hardenberg, M. C. et al. Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies. bioRxiv https://doi.org/10.1101/2020.06.08.140798 (2020).

    Article  Google Scholar 

  219. Mayer, R. J. et al. Ubiquitin, lysosomes and neurodegenerative diseases. Biochem. Soc. Trans. 20, 645–648 (1992).

    CAS  PubMed  Google Scholar 

  220. Koffie, R. M. et al. Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc. Natl Acad. Sci. USA 106, 4012–4017 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Dickson, D. W., Uchikado, H., Fujishiro, H. & Tsuboi, Y. Evidence in favor of Braak staging of Parkinson’s disease. Mov. Disord. 25, S78–S82 (2010).

    PubMed  Google Scholar 

  222. Jellinger, K. A. Alpha-synuclein pathology in Parkinson’s and Alzheimer’s disease brain: incidence and topographic distribution–a pilot study. Acta Neuropathol. 106, 191–201 (2003).

    PubMed  Google Scholar 

  223. Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 14, 501–503 (2008). This study along the work by Kordower et al. (Nat. Med., 2008) provides the first evidence that PD pathology can propagate from host to graft cell, as evidenced by the presence of LBs and LNs in grafted neurons, thus paving the way for new experimental approaches and hypotheses on the mechanisms of α-syn pathology spreading in the brain.

    CAS  PubMed  Google Scholar 

  224. Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat. Med. 14, 504–506 (2008).

    CAS  PubMed  Google Scholar 

  225. Chu, Y. & Kordower, J. H. Lewy body pathology in fetal grafts. Ann. N. Y. Acad. Sci. 1184, 55–67 (2010).

    CAS  PubMed  Google Scholar 

  226. Kordower, J. H., Chu, Y., Hauser, R. A., Olanow, C. W. & Freeman, T. B. Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov. Disord. 23, 2303–2306 (2008).

    PubMed  Google Scholar 

  227. Li, J. Y. et al. Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson’s disease. Mov. Disord. 25, 1091–1096 (2010).

    PubMed  Google Scholar 

  228. Volpicelli-Daley, L. A. et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57–71 (2011). This study demonstrates that exogenous addition of PFFs to primary hippocampal neurons leads to seeding and formation of filamentous structures that are positive for several markers of LBs, such as pS129 α-syn, ubiquitin and p62, and formation of insoluble α-syn aggregates, a phenotype that was accompanied by synaptic dysfunction and cell death.

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Volpicelli-Daley, L. A., Luk, K. C. & Lee, V. M. Addition of exogenous α-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to Lewy body and Lewy neurite-like aggregates. Nat. Protoc. 9, 2135–2146 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Volpicelli-Daley, L. A. et al. Formation of α-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes. Mol. Biol. Cell 25, 4010–4023 (2014).

    PubMed  PubMed Central  Google Scholar 

  231. Wu, Q. et al. α-Synuclein (αSyn) preformed fibrils induce endogenous αSyn aggregation, compromise synaptic activity and enhance synapse loss in cultured excitatory hippocampal neurons. J. Neurosci. 39, 5080–5094 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Luk, K. C. et al. Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Natl Acad. Sci. USA 106, 20051–20056 (2009). This study demonstrates that exogenous addition of PFFs to cultured cells leads to seeding and formation of inclusions that recapitulate several key features of LBs, including being fibrillar, insoluble, hyperphosphorylated and ubiquitinated.

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Guo, J. L. et al. Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell 154, 103–117 (2013).

    CAS  PubMed  Google Scholar 

  235. Nonaka, T., Watanabe, S. T., Iwatsubo, T. & Hasegawa, M. Seeded aggregation and toxicity of α-synuclein and tau: cellular models of neurodegenerative diseases. J. Biol. Chem. 285, 34885–34898 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Tran, H. T. et al. α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 7, 2054–2065 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Waxman, E. A. & Giasson, B. I. Induction of intracellular tau aggregation is promoted by α-synuclein seeds and provides novel insights into the hyperphosphorylation of tau. J. Neurosci. 31, 7604–7618 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Burtscher, J., Copin, J. C., Sandi, C. & Lashuel, H. A. Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala. eNeuro https://doi.org/10.1523/ENEURO.0110-20.2020 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Luk, K. C. et al. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J. Exp. Med. 209, 975–986 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Mahul-Mellier, A.-L. et al. The making of a Lewy body: the role of α-synuclein post-fibrillization modifications in regulating the formation and the maturation of pathological inclusions. bioRxiv https://doi.org/10.1101/500058 (2018). This study establishes the critical role of postfibrillization C-terminal truncation in the processing of α-syn fibrils, α-syn seeding, fibrillization, and LB formation and maturation.

  242. Mougenot, A. L. et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol. Aging 33, 2225–2228 (2012).

    CAS  PubMed  Google Scholar 

  243. Watts, J. C. et al. Transmission of multiple system atrophy prions to transgenic mice. Proc. Natl Acad. Sci. USA 110, 19555–19560 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Schweighauser, M. et al. Formaldehyde-fixed brain tissue from spontaneously ill α-synuclein transgenic mice induces fatal α-synucleinopathy in transgenic hosts. Acta Neuropathol. 129, 157–159 (2015).

    PubMed  Google Scholar 

  245. Sacino, A. N. et al. Brain injection of α-synuclein induces multiple proteinopathies, gliosis, and a neuronal injury marker. J. Neurosci. 34, 12368–12378 (2014).

    PubMed  PubMed Central  Google Scholar 

  246. Sacino, A. N. et al. Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein. Acta Neuropathol. Commun. 1, 38 (2013).

    PubMed  PubMed Central  Google Scholar 

  247. Masuda-Suzukake, M. et al. Pathological α-synuclein propagates through neural networks. Acta Neuropathol. Commun. 2, 88 (2014).

    PubMed  PubMed Central  Google Scholar 

  248. Masuda-Suzukake, M. et al. Prion-like spreading of pathological alpha-synuclein in brain. Brain 136, 1128–1138 (2013).

    PubMed  PubMed Central  Google Scholar 

  249. Tarutani, A. et al. The effect of fragmented pathogenic α-synuclein seeds on prion-like propagation. J. Biol. Chem. 291, 18675–18688 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Recasens, A. et al. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann. Neurol. 75, 351–362 (2014).

    CAS  PubMed  Google Scholar 

  251. Luk, K. C. et al. Molecular and biological compatibility with host α-synuclein influences fibril pathogenicity. Cell Rep. 16, 3373–3387 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Rey, N. L. et al. Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J. Exp. Med. 213, 1759–1778 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Thakur, P. et al. Modeling Parkinson’s disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain. Proc. Natl Acad. Sci. USA 114, E8284–E8293 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. Shimozawa, A. et al. Propagation of pathological α-synuclein in marmoset brain. Acta Neuropathol. Commun. 5, 12 (2017).

    PubMed  PubMed Central  Google Scholar 

  255. Chu, Y. et al. Intrastriatal α-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes. Brain 142, 3565–3579 (2019).

    PubMed  PubMed Central  Google Scholar 

  256. Bourdenx, M. et al. Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates. Sci. Adv. 6, eaaz9165 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Pieri, L., Madiona, K. & Melki, R. Structural and functional properties of prefibrillar α-synuclein oligomers. Sci. Rep. 6, 24526 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Marques, O. & Outeiro, T. F. α-synuclein: from secretion to dysfunction and death. Cell Death Dis. 3, e350 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Agnati, L. F. et al. A new hypothesis of pathogenesis based on the divorce between mitochondria and their host cells: possible relevance for Alzheimer’s disease. Curr. Alzheimer Res. 7, 307–322 (2010).

    CAS  PubMed  Google Scholar 

  260. Lee, H. J., Patel, S. & Lee, S. J. Intravesicular localization and exocytosis of α-synuclein and its aggregates. J. Neurosci. 25, 6016–6024 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Lee, H. J. et al. Dopamine promotes formation and secretion of non-fibrillar α-synuclein oligomers. Exp. Mol. Med. 43, 216–222 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  262. Jang, A. et al. Non-classical exocytosis of α-synuclein is sensitive to folding states and promoted under stress conditions. J. Neurochem. 113, 1263–1274 (2010).

    CAS  PubMed  Google Scholar 

  263. Hasegawa, T. et al. The AAA-ATPase VPS4 regulates extracellular secretion and lysosomal targeting of α-synuclein. PLoS ONE 6, e29460 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. Liu, J. et al. Rab11a and HSP90 regulate recycling of extracellular α-synuclein. J. Neurosci. 29, 1480–1485 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. Alvarez-Erviti, L. et al. Lysosomal dysfunction increases exosome-mediated α-synuclein release and transmission. Neurobiol. Dis. 42, 360–367 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  266. Emmanouilidou, E. et al. Cell-produced α-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J. Neurosci. 30, 6838–6851 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  267. Danzer, K. M. et al. Exosomal cell-to-cell transmission of α synuclein oligomers. Mol. Neurodegener. 7, 42 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  268. Guo, J. L. & Lee, V. M. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat. Med. 20, 130–138 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Mahul-Mellier, A. L. et al. Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death. Cell Death Differ. 22, 2107–2122 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Volles, M. J. & Lansbury, P. T. Jr Vesicle permeabilization by protofibrillar α-synuclein is sensitive to Parkinson’s disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 41, 4595–4602 (2002).

    CAS  PubMed  Google Scholar 

  271. Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T. & Lansbury, P. T. Jr. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291 (2002).

    CAS  PubMed  Google Scholar 

  272. Quist, A. et al. Amyloid ion channels: a common structural link for protein-misfolding disease. Proc. Natl Acad. Sci. USA 102, 10427–10432 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  273. Pountney, D. L., Voelcker, N. H. & Gai, W. P. Annular α-synuclein oligomers are potentially toxic agents in α-synucleinopathy. Hypothesis. Neurotox. Res. 7, 59–67 (2005).

    CAS  PubMed  Google Scholar 

  274. Tsigelny, I. F. et al. Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation. FEBS J. 279, 1000–1013 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  275. Ouberai, M. M. et al. α-Synuclein senses lipid packing defects and induces lateral expansion of lipids leading to membrane remodeling. J. Biol. Chem. 288, 20883–20895 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. Kayed, R. et al. Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J. Biol. Chem. 279, 46363–46366 (2004).

    CAS  PubMed  Google Scholar 

  277. Reynolds, N. P. et al. Mechanism of membrane interaction and disruption by α-synuclein. J. Am. Chem. Soc. 133, 19366–19375 (2011).

    CAS  PubMed  Google Scholar 

  278. Hellstrand, E., Nowacka, A., Topgaard, D., Linse, S. & Sparr, E. Membrane lipid co-aggregation with α-synuclein fibrils. PLoS ONE 8, e77235 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  279. Varkey, J. et al. Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins. J. Biol. Chem. 285, 32486–32493 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  280. Pandey, A. P., Haque, F., Rochet, J. C. & Hovis, J. S. α-Synuclein-induced tubule formation in lipid bilayers. J. Phys. Chem. B 115, 5886–5893 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  281. Holmes, B. B. et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc. Natl Acad. Sci. USA 110, E3138–E3147 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  282. Hansen, C. et al. α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121, 715–725 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  283. Lee, H. J., Bae, E. J. & Lee, S. J. Extracellular α-synuclein-a novel and crucial factor in Lewy body diseases. Nat. Rev. Neurol. 10, 92–98 (2014).

    CAS  PubMed  Google Scholar 

  284. Weissmann, C., Enari, M., Klohn, P. C., Rossi, D. & Flechsig, E. Transmission of prions. Proc. Natl Acad. Sci. USA 99, 16378–16383 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  285. Dujardin, S. et al. Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease. Nat. Med. 26, 1256–1263 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  286. Bauerlein, F. J. B. et al. In situ architecture and cellular interactions of PolyQ inclusions. Cell 171, 179–187.e10 (2017).

    PubMed  Google Scholar 

  287. Mamais, A. et al. Divergent α-synuclein solubility and aggregation properties in G2019S LRRK2 Parkinson’s disease brains with Lewy Body pathology compared to idiopathic cases. Neurobiol. Dis. 58, 183–190 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  288. Spillantini, M. G. et al. Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 251, 205–208 (1998).

    CAS  PubMed  Google Scholar 

  289. Halliday, G. et al. Milestones in Parkinson’s disease — clinical and pathologic features. Mov. Disord. 26, 1015–1021 (2011).

    PubMed  Google Scholar 

  290. Lashuel, H. A. et al. α-synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. J. Mol. Biol. 322, 1089–1102 (2002).

    CAS  PubMed  Google Scholar 

  291. Dhillon, S. J.-K. et al. A novel panel of α-synuclein antibodies reveal distinctive staining profiles in synucleinopathies. PLoS ONE 12, e0184731 (2017).

    PubMed  PubMed Central  Google Scholar 

  292. Gründemann, J., Schlaudraff, F., Haeckel, O. & Liss, B. Elevated α-synuclein mRNA levels in individual UV-laser-microdissected dopaminergic substantia nigra neurons in idiopathic Parkinson’s disease. Nucleic Acids Res. 36, e38 (2008).

    PubMed  PubMed Central  Google Scholar 

  293. Glaab, E. & Schneider, R. Comparative pathway and network analysis of brain transcriptome changes during adult aging and in Parkinson’s disease. Neurobiol. Aging 74, 1–13 (2015).

    CAS  Google Scholar 

  294. Hernandez, S. M., Tikhonova, E. B. & Karamyshev, A. L. Protein–protein interactions in α-synuclein biogenesis: new potential targets in Parkinson’s disease. Front. Aging Neurosci. 12, 72 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  295. Wood, S. J. et al. α-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson’s disease. J. Biol. Chem. 274, 19509–19512 (1999).

    CAS  PubMed  Google Scholar 

  296. Qin, Z., Hu, D., Han, S., Hong, D. P. & Fink, A. L. Role of different regions of α-synuclein in the assembly of fibrils. Biochemistry 46, 13322–13330 (2007).

    CAS  PubMed  Google Scholar 

  297. Conway, K. A., Harper, J. D. & Lansbury, P. T. Jr Fibrils formed in vitro from α-synuclein and two mutant forms linked to Parkinson’s disease are typical amyloid. Biochemistry 39, 2552–2563 (2000).

    CAS  PubMed  Google Scholar 

  298. Giasson, B. I., Uryu, K., Trojanowski, J. Q. & Lee, V. M. Mutant and wild type human α-synucleins assemble into elongated filaments with distinct morphologies in vitro. J. Biol. Chem. 274, 7619–7622 (1999).

    CAS  PubMed  Google Scholar 

  299. Harper, J. D. & Lansbury, P. T. Jr Models of amyloid seeding in Alzheimer’s disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu. Rev. Biochem. 66, 385–407 (1997).

    CAS  PubMed  Google Scholar 

  300. Bousset, L. et al. Structural and functional characterization of two α-synuclein strains. Nat. Commun. 4, 2575 (2013).

    PubMed  Google Scholar 

  301. Peelaerts, W. et al. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340–344 (2015).

    CAS  PubMed  Google Scholar 

  302. Gribaudo, S. et al. Propagation of α-synuclein strains within human reconstructed neuronal network. Stem Cell Rep. 12, 230–244 (2019).

    CAS  Google Scholar 

  303. Guerrero-Ferreira, R. et al. Two new polymorphic structures of α-synuclein solved by cryo-electron microscopy. bioRxiv https://doi.org/10.1101/654582 (2019).

    Article  Google Scholar 

  304. Guerrero-Ferreira, R. et al. Cryo-EM structure of α-synuclein fibrils. eLife 7, e36402 (2018).

    PubMed  PubMed Central  Google Scholar 

  305. Boyer, D. R. et al. The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure. Proc. Natl Acad. Sci. USA 117, 3592–3602 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  306. Boyer, D. R. et al. Cryo-EM structures of α-synuclein fibrils with the H50Q hereditary mutation reveal new polymorphs. bioRxiv https://doi.org/10.1101/738450 (2019).

    Article  Google Scholar 

  307. Schweighauser, M. et al. Structures of α-synuclein filaments from multiple system atrophy. bioRxiv https://doi.org/10.1101/2020.02.05.935619 (2020).

    Article  Google Scholar 

  308. Strohäker, T. et al. Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts. Nat. Commun. 10, 5535 (2019).

    PubMed  PubMed Central  Google Scholar 

  309. Shahnawaz, M. et al. Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature 578, 273–277 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are grateful to A.-L. Mahul-Mellier, R. Hegde, S. Donzelli, S. Novello, I. Rostami and N. Riguet for their critical inputs regarding supplementary tables 2 and 3, and thank G. Limorenko, R. Hegde and S. Novello for help in revising galley proofs.

Author information

Author notes

  1. These authors contributed equally: Mohamed Bilal Fares, Somanath Jagannath and Hilal A. Lashuel.

Authors and Affiliations

  1. Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Mohamed Bilal Fares, Somanath Jagannath & Hilal A. Lashuel

  2. ND BioSciences, Epalinges, Switzerland

    Mohamed Bilal Fares & Hilal A. Lashuel

Authors
  1. Mohamed Bilal Fares
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Somanath Jagannath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hilal A. Lashuel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Mohamed Bilal Fares or Hilal A. Lashuel.

Ethics declarations

Competing interests

H.A.L. has received funding from industry to support research on neurodegenerative diseases, including from Merck Serono, UCB and Abbvie. These companies had no specific role in the in the conceptualization and preparation of and decision to publish this work. H.A.L is also the co-founder and Chief Scientific Officer of ND BioSciences SA, a company that develops diagnostics and treatments for neurodegenerative diseases based on platforms that reproduce the complexity and diversity of proteins implicated in neurodegenerative diseases and their pathologies. M.B.F. is a co-founder of ND BioSciences SA and Director of Research and Development in the company. S.J. declares no competing interests.

Additional information

Peer review information

Nature Reviews Neuroscience thanks S. Gentleman, M. Hasegawa and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Inclusions

A term commonly used to describe the localized accumulation of proteins in cells or tissues as determined by their immunoreactivity to specific antibodies or detection of fluorescent puncta when the protein of interest is fused to fluorescent proteins. Not all inclusions represent the accumulation of aggregated proteins, unless verified by other biophysical or biochemical techniques.

Lewy bodies

(LBs). One of the key pathological hallmarks of Parkinson disease and other synucleinopathies. They comprise intracellular globular cytoplasmic inclusions that contain complex mixtures of proteins, lipids and membranous organelles, and are enriched in aggregated forms of α-synuclein, predominantly insoluble fibrillar species.

Lewy neurites

(LNs). A pathological hallmark of Parkinson disease. These are dystrophic processes containing protein accumulations that share many of the biochemical and immunohistological properties of Lewy bodies, including the presence of phosphorylated filamentous α-synuclein aggregates, although their ultrastructural features and biochemical composition remain less well characterized.

Propagation

A term that refers to the process underlying the spreading of pathological aggregates in the brain through the transfer of seeding-competent protein aggregates from one cell to another.

Oligomers

Soluble peptide or protein assemblies (dimers or multimers) that exhibit different sizes, secondary structures and shapes (for example, spherical, pore-like and curvilinear structures).

Fibrils

Insoluble filamentous structures (8–12 nm in diameter) that form as a result of the misfolding and self-assembly of a peptide or a protein (for example, α-synuclein) via formation of repeating β-sheet structures, also known as cross-β structure, which is responsible for their unique binding to specific dyes (for example, thioflavin T, thioflavin S, Amytracker and Congo red), and allows them to be distinguished from other β-sheet-rich proteins.

Amorphous aggregates

Aberrant protein aggregates that do not exhibit a specific ordered organization or morphology, that is, they are non-fibrillar.

Pale bodies

Usually referred to as precursors to Lewy bodies, pale bodies are proteinaceous accumulations enriched with aggregated α-synuclein but do not exhibit many of the morphological, organizational and biochemical properties of mature Lewy bodies.

Seeds

Relatively stable aggregates that can be prepared in vitro (such as fragmented fibrils) or isolated from pathological inclusions (such as Lewy bodies or glial cytoplasmic inclusions), total brain homogenates or the cerebrospinal fluid of patients with Parkinson disease or other synucleinopathies. When added to solutions or cells that have monomeric α-syn subunits, seeds accelerate their conversion to fibrils (in vitro) or to fibrils and Lewy body-like structures in neurons.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fares, M.B., Jagannath, S. & Lashuel, H.A. Reverse engineering Lewy bodies: how far have we come and how far can we go?. Nat Rev Neurosci 22, 111–131 (2021). https://doi.org/10.1038/s41583-020-00416-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41583-020-00416-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing