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Key genes and convergent pathogenic mechanisms in Parkinson disease

Nature Reviews Neuroscience (2024)Cite this article

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Abstract

Parkinson disease (PD) is a neurodegenerative disorder marked by the preferential dysfunction and death of dopaminergic neurons in the substantia nigra. The onset and progression of PD is influenced by a diversity of genetic variants, many of which lack functional characterization. To identify the most high-yield targets for therapeutic intervention, it is important to consider the core cellular compartments and functional pathways upon which the varied forms of pathogenic dysfunction may converge. Here, we review several key PD-linked proteins and pathways, focusing on the mechanisms of their potential convergence in disease pathogenesis. These dysfunctions primarily localize to a subset of subcellular compartments, including mitochondria, lysosomes and synapses. We discuss how these pathogenic mechanisms that originate in different cellular compartments may coordinately lead to cellular dysfunction and neurodegeneration in PD.

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Fig. 1: Convergent cellular functions of Parkinson disease-related proteins.
Fig. 2: Synaptic functions of Parkinson disease-related proteins.
Fig. 3: Interorganelle contacts in physiological and pathological contexts.

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References

  1. Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Prim. 3, 17013 (2017).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  3. Jankovic, J. Parkinson’s disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 79, 368–376 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Blauwendraat, C., Nalls, M. A. & Singleton, A. B. The genetic architecture of Parkinson’s disease. Lancet Neurol. 19, 170–178 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Jia, F., Fellner, A. & Kumar, K. R. Monogenic Parkinson’s disease: genotype, phenotype, pathophysiology, and genetic testing. Genes 13, 471 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091–1102 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kim, J. J. et al. Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease. Nat. Genet. 56, 27–36 (2024).

    Article  CAS  PubMed  Google Scholar 

  8. Rizig, M. et al. Identification of genetic risk loci and causal insights associated with Parkinson’s disease in African and African admixed populations: a genome-wide association study. Lancet Neurol. 22, 1015–1025 (2023).

    Article  CAS  PubMed  Google Scholar 

  9. Ball, N., Teo, W. P., Chandra, S. & Chapman, J. Parkinson’s disease and the environment. Front. Neurol. 10, 218 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Tansey, M. G. et al. Inflammation and immune dysfunction in Parkinson disease. Nat. Rev. Immunol. 22, 657–673 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kam, T. I., Hinkle, J. T., Dawson, T. M. & Dawson, V. L. Microglia and astrocyte dysfunction in Parkinson’s disease. Neurobiol. Dis. 144, 105028 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bjorklund, G., Hofer, T., Nurchi, V. M. & Aaseth, J. Iron and other metals in the pathogenesis of Parkinson’s disease: toxic effects and possible detoxification. J. Inorg. Biochem. 199, 110717 (2019).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Singleton, A. B. et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302, 841 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Giasson, B. I., Murray, I. V., Trojanowski, J. Q. & Lee, V. M. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J. Biol. Chem. 276, 2380–2386 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Conway, K. A., Harper, J. D. & Lansbury, P. T. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat. Med. 4, 1318–1320 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Masliah, E. et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265–1269 (2000). This work is, to our knowledge, the first to model overexpression of human α-synuclein in mice, which developed Lewy body-like inclusions, dopaminergic neuron terminal loss and motor deficits.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Burre, J. et al. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329, 1663–1667 (2010). This paper provides evidence for a physiological role of α-synuclein in SNARE complex assembly through association with VAMP2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nemani, V. M. et al. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65, 66–79 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Runwal, G. M. & Edwards, R. H. The role of alpha-synuclein in exocytosis. Exp. Neurol. 373, 114668 (2024).

    Article  CAS  PubMed  Google Scholar 

  23. Wong, Y. C. & Krainc, D. α-Synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat. Med. 23, 1–13 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vogiatzi, T., Xilouri, M., Vekrellis, K. & Stefanis, L. Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J. Biol. Chem. 283, 23542–23556 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Robak, L. A. et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain 140, 3191–3203 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sevlever, D., Jiang, P. & Yen, S. H. Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species. Biochemistry 47, 9678–9687 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Qiao, L. et al. Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol. Brain 1, 17 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Chang, D. et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat. Genet. 49, 1511–1516 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. McGlinchey, R. P. & Lee, J. C. Cysteine cathepsins are essential in lysosomal degradation of alpha-synuclein. Proc. Natl Acad. Sci. USA 112, 9322–9327 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Manzanza, N. O., Sedlackova, L. & Kalaria, R. N. Alpha-synuclein post-translational modifications: implications for pathogenesis of Lewy body disorders. Front. Aging Neurosci. 13, 690293 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Souza, J. M., Giasson, B. I., Chen, Q., Lee, V. M. & Ischiropoulos, H. Dityrosine cross-linking promotes formation of stable alpha-synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J. Biol. Chem. 275, 18344–18349 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Fujiwara, H. et al. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160–164 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Mahul-Mellier, A. L. et al. c-Abl phosphorylates alpha-synuclein and regulates its degradation: implication for alpha-synuclein clearance and contribution to the pathogenesis of Parkinson’s disease. Hum. Mol. Genet. 23, 2858–2879 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Burmann, B. M. et al. Regulation of alpha-synuclein by chaperones in mammalian cells. Nature 577, 127–132 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Valente, E. M. et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Pickrell, A. M. & Youle, R. J. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85, 257–273 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li, J. et al. PINK1/parkin-mediated mitophagy in neurodegenerative diseases. Ageing Res. Rev. 84, 101817 (2023).

    Article  CAS  PubMed  Google Scholar 

  41. Meissner, C., Lorenz, H., Weihofen, A., Selkoe, D. J. & Lemberg, M. K. The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J. Neurochem. 117, 856–867 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010). This key early paper in the mitophagy field establishes that mitochondrial depolarization impairs the proteolytic processing of PINK1, resulting in its stable association with the outer mitochondrial membrane and the recruitment of parkin in a manner dependent on its kinase activity.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kondapalli, C. et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates parkin E3 ligase activity by phosphorylating serine 65. Open Biol. 2, 120080 (2012). This paper demonstrates that PINK1 phosphorylation of parkin is a critical modification for the activation of parkin ubiquitin ligase activity in the early stages of mitophagy.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Koyano, F. et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510, 162–166 (2014). In this paper, the authors found that ubiquitin phosphorylation by PINK1 facilitates the alleviation of parkin autoinhibition, rounding out our understanding of the broad mechanistic details of PINK1/parkin-mediated initiation of mitophagy.

    Article  CAS  PubMed  Google Scholar 

  45. Kim, N. C. et al. VCP is essential for mitochondrial quality control by PINK1/parkin and this function is impaired by VCP mutations. Neuron 78, 65–80 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ziviani, E., Tao, R. N. & Whitworth, A. J. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc. Natl Acad. Sci. USA 107, 5018–5023 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chan, N. C. et al. Broad activation of the ubiquitin-proteasome system by parkin is critical for mitophagy. Hum. Mol. Genet. 20, 1726–1737 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chen, Y. & Dorn, G. W. II PINK1-phosphorylated mitofusin 2 is a parkin receptor for culling damaged mitochondria. Science 340, 471–475 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang, X. et al. PINK1 and parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147, 893–906 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Twig, G., Hyde, B. & Shirihai, O. S. Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim. Biophys. Acta 1777, 1092–1097 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Wong, Y. C. & Holzbaur, E. L. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc. Natl Acad. Sci. USA 111, E4439–E4448 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309–314 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sarraf, S. A. et al. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496, 372–376 (2013). Various proteomic experiments conducted in this paper provide a large dataset of parkin-dependent ubiquitylation sites across the human proteome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Di Fonzo, A. et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology 72, 240–245 (2009).

    Article  PubMed  Google Scholar 

  55. Burchell, V. S. et al. The Parkinson’s disease-linked proteins Fbxo7 and parkin interact to mediate mitophagy. Nat. Neurosci. 16, 1257–1265 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Liu, Y. et al. Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1. JCI Insight 5, e131834 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Kraus, F. et al. PARK15/FBXO7 is dispensable for PINK1/parkin mitophagy in iNeurons and HeLa cell systems. EMBO Rep. 24, e56399 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Do, C. B. et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genet. 7, e1002141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ivatt, R. M. et al. Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy. Proc. Natl Acad. Sci. USA 111, 8494–8499 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bonifati, V. et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256–259 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Lee, J. Y. et al. Human DJ-1 and its homologs are novel glyoxalases. Hum. Mol. Genet. 21, 3215–3225 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Allaman, I., Belanger, M. & Magistretti, P. J. Methylglyoxal, the dark side of glycolysis. Front. Neurosci. 9, 23 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Wilson, M. A., Collins, J. L., Hod, Y., Ringe, D. & Petsko, G. A. The 1.1-A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson’s disease. Proc. Natl Acad. Sci. USA 100, 9256–9261 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yokota, T. et al. Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem. Biophys. Res. Commun. 312, 1342–1348 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Canet-Aviles, R. M. et al. The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc. Natl Acad. Sci. USA 101, 9103–9108 (2004). This early paper on the characterization of the role of PARK7 in PD demonstrates that PD-associated chemical insults promote the relocalization of PARK7 to the outer mitochondrial membrane in a manner dependent on the ability of residue C106 to be oxidized.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W. & Ting, J. P. DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc. Natl Acad. Sci. USA 103, 15091–15096 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kim, R. H. et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc. Natl Acad. Sci. USA 102, 5215–5220 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Thomas, K. J. et al. DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum. Mol. Genet. 20, 40–50 (2011). To our knowledge, this is the first paper to suggest a relationship between PARK7 and PINK1/parkin mitophagy, proposing parallel contributions to mitochondrial health based on reciprocal rescue of PINK1 or PARK7 loss by overexpression of the other in a dopaminergic neuroblastoma cell line.

    Article  CAS  PubMed  Google Scholar 

  69. Imberechts, D. et al. DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy. Brain 145, 4368–4384 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Shendelman, S., Jonason, A., Martinat, C., Leete, T. & Abeliovich, A. DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol. 2, e362 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Konig, A., Vicente Miranda, H. & Outeiro, T. F. Alpha-synuclein glycation and the action of anti-diabetic agents in Parkinson’s disease. J. Parkinsons Dis. 8, 33–43 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Mencke, P. et al. The role of DJ-1 in cellular metabolism and pathophysiological implications for Parkinson’s disease. Cells 10, 347 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zimprich, A. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Smith, W. W. et al. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat. Neurosci. 9, 1231–1233 (2006). This paper establishes LRRK2 kinase hyperactivation as a key source of neuronal toxicity produced by PD-linked LRRK2 mutations.

    Article  CAS  PubMed  Google Scholar 

  75. West, A. B. et al. Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet. 16, 223–232 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Lin, X. et al. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant alpha-synuclein. Neuron 64, 807–827 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Di Maio, R. et al. LRRK2 activation in idiopathic Parkinson’s disease. Sci. Transl. Med. 10, eaar5429 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Fernandez, B. et al. Evaluation of current methods to detect cellular leucine-rich repeat kinase 2 (LRRK2) kinase activity. J. Parkinsons Dis. 12, 1423–1447 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Moehle, M. S. et al. LRRK2 inhibition attenuates microglial inflammatory responses. J. Neurosci. 32, 1602–1611 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. di Domenico, A. et al. Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson’s disease. Stem Cell Rep. 12, 213–229 (2019).

    Article  Google Scholar 

  81. Yadavalli, N. & Ferguson, S. M. LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition. Proc. Natl Acad. Sci. USA 120, e2303789120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Alegre-Abarrategui, J. et al. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum. Mol. Genet. 18, 4022–4034 (2009). The finding of this paper — that LRRK2 can localize to autophagic vesicles to negatively regulate autophagy — has shaped a significant amount of the research related to the role of LRRK2 in PD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Berwick, D. C., Heaton, G. R., Azeggagh, S. & Harvey, K. LRRK2 biology from structure to dysfunction: research progresses, but the themes remain the same. Mol. Neurodegener. 14, 49 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bonet-Ponce, L. et al. LRRK2 mediates tubulation and vesicle sorting from lysosomes. Sci. Adv. 6, eabb2454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kluss, J. H., Bonet-Ponce, L., Lewis, P. A. & Cookson, M. R. Directing LRRK2 to membranes of the endolysosomal pathway triggers RAB phosphorylation and JIP4 recruitment. Neurobiol. Dis. 170, 105769 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Steger, M. et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 5, e12813 (2016). The phosphoproteomic dataset of LRRK2 substrates produced in this work identifies several RAB proteins as key targets.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Steger, M. et al. Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. eLife 6, e31012 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Vides, E. G. et al. A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation. eLife 11, e79771 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Dhekne, H. S. et al. Genome-wide screen reveals Rab12 GTPase as a critical activator of Parkinson’s disease-linked LRRK2 kinase. eLife 12, e87098 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Wang, X. et al. Rab12 is a regulator of LRRK2 and its activation by damaged lysosomes. eLife 12, e87255 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Herbst, S. et al. LRRK2 activation controls the repair of damaged endomembranes in macrophages. EMBO J. 39, e104494 (2020). This recent work provides mechanistic evidence for a physiological role of LRRK2 in membrane repair processes initiated upon lysosomal damage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gan-Or, Z. et al. Association of sequence alterations in the putative promoter of RAB7L1 with a reduced Parkinson disease risk. Arch. Neurol. 69, 105–110 (2012).

    Article  PubMed  Google Scholar 

  93. MacLeod, D. A. et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron 77, 425–439 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Purlyte, E. et al. Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase. EMBO J. 37, 1–18 (2018).

    Article  CAS  PubMed  Google Scholar 

  95. Kalogeropulou, A. F. et al. Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity. Biochem. J. 477, 4397–4423 (2020).

    Article  CAS  PubMed  Google Scholar 

  96. Beilina, A. et al. Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc. Natl Acad. Sci. USA 111, 2626–2631 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Pankratz, N. et al. Meta-analysis of Parkinson’s disease: identification of a novel locus, RIT2. Ann. Neurol. 71, 370–384 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Obergasteiger, J. et al. The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology. NPJ Parkinsons Dis. 9, 44 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Vilarino-Guell, C. et al. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89, 162–167 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Zimprich, A. et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168–175 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Follett, J. et al. The Vps35 D620N mutation linked to Parkinson’s disease disrupts the cargo sorting function of retromer. Traffic 15, 230–244 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. McGough, I. J. et al. Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation. Curr. Biol. 24, 1678 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zavodszky, E. et al. Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat. Commun. 5, 3828 (2014). Although the pathological role of the VPS35 mutation in PD is still being clarified, the finding described in this paper — that the D620N mutation impairs the association of the retromer complex with the WASH complex — offers a potential direction for more mechanistic insight.

    Article  CAS  PubMed  Google Scholar 

  104. Daly, J. L. et al. Multi-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health. Nat. Commun. 14, 3086 (2023). The multi-omic dataset produced in this paper shows severe changes to the composition of lysosomes upon knockout of VPS35, bolstering the associations being made between VPS35 and lysosomal function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Paisan-Ruiz, C. et al. Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann. Neurol. 65, 19–23 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Lin, G. et al. Phospholipase PLA2G6, a Parkinsonism-associated gene, affects Vps26 and Vps35, retromer function, and ceramide levels, similar to alpha-synuclein gain. Cell Metab. 28, 605–618.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  107. Chiu, C. C. et al. PARK14 (D331Y) PLA2G6 causes early-onset degeneration of substantia nigra dopaminergic neurons by inducing mitochondrial dysfunction, ER stress, mitophagy impairment and transcriptional dysregulation in a knockin mouse model. Mol. Neurobiol. 56, 3835–3853 (2019).

    Article  CAS  PubMed  Google Scholar 

  108. Tayebi, N. et al. Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol. Genet. Metab. 79, 104–109 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Sidransky, E. et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N. Engl. J. Med. 361, 1651–1661 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mazzulli, J. R. et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146, 37–52 (2011). This paper identifies a pathogenic feedforward mechanism between α-synuclein accumulation and the impaired trafficking and lysosomal activity of GBA1, offering a potential key point of convergent dysfunction in the pathogenesis of PD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Burbulla, L. F. et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357, 1255–1261 (2017). The experiments in this work identify the production of oxidized dopamine in iPSC-derived dopaminergic neurons across a variety of genetic PD models as a key pathologic event influencing the accumulation of insoluble α-synuclein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Nguyen, M. & Krainc, D. LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson’s disease. Proc. Natl Acad. Sci. USA 115, 5576–5581 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ysselstein, D. et al. LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients. Nat. Commun. 10, 5570 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Murphy, K. E. et al. Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson’s disease. Brain 137, 834–848 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Taguchi, Y. V. et al. Glucosylsphingosine promotes alpha-synuclein pathology in mutant GBA-associated Parkinson’s disease. J. Neurosci. 37, 9617–9631 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rocha, E. M. et al. Progressive decline of glucocerebrosidase in aging and Parkinson’s disease. Ann. Clin. Transl. Neurol. 2, 433–438 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Gegg, M. E. et al. Glucocerebrosidase deficiency in substantia nigra of Parkinson disease brains. Ann. Neurol. 72, 455–463 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ramirez, A. et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38, 1184–1191 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Dehay, B. et al. Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc. Natl Acad. Sci. USA 109, 9611–9616 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Tsunemi, T., Hamada, K. & Krainc, D. ATP13A2/PARK9 regulates secretion of exosomes and alpha-synuclein. J. Neurosci. 34, 15281–15287 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Gitler, A. D. et al. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat. Genet. 41, 308–315 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tsunemi, T. & Krainc, D. Zn2+ dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation. Hum. Mol. Genet. 23, 2791–2801 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. van Veen, S. et al. ATP13A2 deficiency disrupts lysosomal polyamine export. Nature 578, 419–424 (2020).

    Article  PubMed  Google Scholar 

  124. Edvardson, S. et al. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLoS ONE 7, e36458 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Krebs, C. E. et al. The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive parkinsonism with generalized seizures. Hum. Mutat. 34, 1200–1207 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Quadri, M. et al. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset parkinsonism. Hum. Mutat. 34, 1208–1215 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Schuske, K. R. et al. Endophilin is required for synaptic vesicle endocytosis by localizing synaptojanin. Neuron 40, 749–762 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Verstreken, P. et al. Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating. Neuron 40, 733–748 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Yim, Y. I. et al. Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice. Proc. Natl Acad. Sci. USA 107, 4412–4417 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Song, L. et al. Auxilin underlies progressive locomotor deficits and dopaminergic neuron loss in a Drosophila model of Parkinson’s disease. Cell Rep. 18, 1132–1143 (2017).

    Article  CAS  PubMed  Google Scholar 

  131. Vanhauwaert, R. et al. The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals. EMBO J. 36, 1392–1411 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Lesage, S. et al. Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/parkin-dependent mitophagy. Am. J. Hum. Genet. 98, 500–513 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Dziurdzik, S. K. & Conibear, E. The Vps13 family of lipid transporters and its role at membrane contact sites. Int. J. Mol. Sci. 22, 2905 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kumar, N. et al. VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites. J. Cell Biol. 217, 3625–3639 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Volpicelli-Daley, L. A. et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57–71 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Winner, B. et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc. Natl Acad. Sci. USA 108, 4194–4199 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chartier, S. & Duyckaerts, C. Is Lewy pathology in the human nervous system chiefly an indicator of neuronal protection or of toxicity? Cell Tissue Res. 373, 149–160 (2018).

    Article  PubMed  Google Scholar 

  138. Schneider, S. A. & Alcalay, R. N. Neuropathology of genetic synucleinopathies with parkinsonism: review of the literature. Mov. Disord. 32, 1504–1523 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Koeglsperger, T. et al. Neuropathology of incidental Lewy body & prodromal Parkinson’s disease. Mol. Neurodegener. 18, 32 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Poulopoulos, M., Levy, O. A. & Alcalay, R. N. The neuropathology of genetic Parkinson’s disease. Mov. Disord. 27, 831–842 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Alim, M. A. et al. Tubulin seeds alpha-synuclein fibril formation. J. Biol. Chem. 277, 2112–2117 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Lee, H. J., Khoshaghideh, F., Lee, S. & Lee, S. J. Impairment of microtubule-dependent trafficking by overexpression of alpha-synuclein. Eur. J. Neurosci. 24, 3153–3162 (2006).

    Article  PubMed  Google Scholar 

  143. 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 work, correlative light and electron microscopy of Lewy pathology in tissue samples from individuals with advanced cases of PD demonstrates the dense sequestration of membranous cellular content, including specific enrichment of mitochondria, lysosomes and autophagosomes.

    Article  CAS  PubMed  Google Scholar 

  144. Liu, G. et al. alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity. Neurosci. Lett. 454, 187–192 (2009).

    Article  CAS  PubMed  Google Scholar 

  145. Wang, X. et al. Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration. Acta Neuropathol. Commun. 7, 41 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Chen, L., Xie, Z., Turkson, S. & Zhuang, X. A53T human alpha-synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration. J. Neurosci. 35, 890–905 (2015).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  148. Chu, Y., Dodiya, H., Aebischer, P., Olanow, C. W. & Kordower, J. H. Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiol. Dis. 35, 385–398 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Dexter, D. T. et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J. Neurochem. 52, 381–389 (1989).

    Article  CAS  PubMed  Google Scholar 

  150. Herrero-Mendez, A. et al. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat. Cell Biol. 11, 747–752 (2009).

    Article  CAS  PubMed  Google Scholar 

  151. Hastings, T. G., Lewis, D. A. & Zigmond, M. J. Role of oxidation in the neurotoxic effects of intrastriatal dopamine injections. Proc. Natl Acad. Sci. USA 93, 1956–1961 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Carballo-Carbajal, I. et al. Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis. Nat. Commun. 10, 973 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Spencer, J. P. et al. Conjugates of catecholamines with cysteine and GSH in Parkinson’s disease: possible mechanisms of formation involving reactive oxygen species. J. Neurochem. 71, 2112–2122 (1998).

    Article  CAS  PubMed  Google Scholar 

  154. Conway, K. A., Rochet, J. C., Bieganski, R. M. & Lansbury, P. T. Jr. Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science 294, 1346–1349 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Junn, E. & Mouradian, M. M. Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci. Lett. 320, 146–150 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Song, P. et al. Parkinson’s disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons. Neuron 111, 3775–3788.e7 (2023).

    Article  CAS  PubMed  Google Scholar 

  157. Martinez-Vicente, M. et al. Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J. Clin. Invest. 118, 777–788 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Plotegher, N. et al. DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function. Sci. Rep. 7, 40699 (2017). This work supports the connection between oxidized dopamine and α-synuclein pathology with the finding that α-synuclein modified by oxidized dopamine has increased oligomerization tendency and may increase synaptic vesicle leakage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Caudle, W. M. et al. Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. J. Neurosci. 27, 8138–8148 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Berman, S. B. & Hastings, T. G. Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J. Neurochem. 73, 1127–1137 (1999).

    Article  CAS  PubMed  Google Scholar 

  161. Graves, S. M. et al. Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain. Nat. Neurosci. 23, 15–20 (2020). This paper establishes a potential connection between oxidized dopamine and mitochondrial dysfunction, finding that cytosolic dopamine oxidized by mitochondrial monoamine oxidase increases electron transport chain activity, resulting in increased generation of mitochondrial ROS.

    Article  CAS  PubMed  Google Scholar 

  162. LaVoie, M. J., Ostaszewski, B. L., Weihofen, A., Schlossmacher, M. G. & Selkoe, D. J. Dopamine covalently modifies and functionally inactivates parkin. Nat. Med. 11, 1214–1221 (2005).

    Article  CAS  PubMed  Google Scholar 

  163. Chung, K. K. et al. S-Nitrosylation of parkin regulates ubiquitination and compromises parkin’s protective function. Science 304, 1328–1331 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. Rizza, S. et al. S-Nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy. Proc. Natl Acad. Sci. USA 115, E3388–E3397 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Oh, C. K. et al. S-Nitrosylation of PINK1 attenuates PINK1/parkin-dependent mitophagy in hiPSC-based Parkinson’s disease models. Cell Rep. 21, 2171–2182 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Girotto, S. et al. Dopamine-derived quinones affect the structure of the redox sensor DJ-1 through modifications at Cys-106 and Cys-53. J. Biol. Chem. 287, 18738–18749 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Hetz, C., Zhang, K. & Kaufman, R. J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 21, 421–438 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Hoozemans, J. J. et al. Activation of the unfolded protein response in Parkinson’s disease. Biochem. Biophys. Res. Commun. 354, 707–711 (2007).

    Article  CAS  PubMed  Google Scholar 

  169. Dukes, A. A., Van Laar, V. S., Cascio, M. & Hastings, T. G. Changes in endoplasmic reticulum stress proteins and aldolase A in cells exposed to dopamine. J. Neurochem. 106, 333–346 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Ryu, E. J. et al. Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease. J. Neurosci. 22, 10690–10698 (2002). This early and influential paper demonstrates that chemical agents associated with PD induce the UPR and, reciprocally, that impairment of the UPR sensitizes neurons to these chemical agents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Holtz, W. A. & O’Malley, K. L. Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons. J. Biol. Chem. 278, 19367–19377 (2003).

    Article  CAS  PubMed  Google Scholar 

  172. Tain, L. S. et al. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat. Neurosci. 12, 1129–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Bouman, L. et al. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ. 18, 769–782 (2011).

    Article  CAS  PubMed  Google Scholar 

  174. Colla, E. et al. Accumulation of toxic alpha-synuclein oligomer within endoplasmic reticulum occurs in alpha-synucleinopathy in vivo. J. Neurosci. 32, 3301–3305 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Coppola-Segovia, V. et al. ER stress induced by tunicamycin triggers alpha-synuclein oligomerization, dopaminergic neurons death and locomotor impairment: a new model of Parkinson’s disease. Mol. Neurobiol. 54, 5798–5806 (2017).

    Article  CAS  PubMed  Google Scholar 

  176. Cooper, A. A. et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313, 324–328 (2006). This paper describes various experiments, performed in yeast and supported in animal models, that point to impaired ER and Golgi trafficking as a key mediator of the toxicity of α-synuclein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Bellucci, A. et al. Induction of the unfolded protein response by alpha-synuclein in experimental models of Parkinson’s disease. J. Neurochem. 116, 588–605 (2011).

    Article  CAS  PubMed  Google Scholar 

  178. Salganik, M. et al. The loss of glucose-regulated protein 78 (GRP78) during normal aging or from siRNA knockdown augments human alpha-synuclein (alpha-syn) toxicity to rat nigral neurons. Neurobiol. Aging 36, 2213–2223 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Gorbatyuk, M. S. et al. Glucose regulated protein 78 diminishes alpha-synuclein neurotoxicity in a rat model of Parkinson disease. Mol. Ther. 20, 1327–1337 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Nguyen, M., Wong, Y. C., Ysselstein, D., Severino, A. & Krainc, D. Synaptic, mitochondrial, and lysosomal dysfunction in Parkinson’s disease. Trends Neurosci. 42, 140–149 (2019).

    Article  CAS  PubMed  Google Scholar 

  181. Diao, J. et al. Native alpha-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. eLife 2, e00592 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Wang, L. et al. α-Synuclein multimers cluster synaptic vesicles and attenuate recycling. Curr. Biol. 24, 2319–2326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Vargas, K. J. et al. Synucleins regulate the kinetics of synaptic vesicle endocytosis. J. Neurosci. 34, 9364–9376 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Matta, S. et al. LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 75, 1008–1021 (2012). This paper reports a potential physiological role of LRRK2 kinase activity at the synapse, modulating the activity of endophilin-A1 to regulate the dynamic process of synaptic vesicle recycling.

    Article  CAS  PubMed  Google Scholar 

  185. Arranz, A. M. et al. LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism. J. Cell Sci. 128, 541–552 (2015).

    CAS  PubMed  Google Scholar 

  186. Soukup, S. F. et al. A LRRK2-dependent EndophilinA phosphoswitch is critical for macroautophagy at presynaptic terminals. Neuron 92, 829–844 (2016).

    Article  CAS  PubMed  Google Scholar 

  187. Islam, M. S. et al. Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson’s disease. Hum. Mol. Genet. 25, 5365–5382 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Pathak, D. et al. The role of mitochondrially derived ATP in synaptic vesicle recycling. J. Biol. Chem. 290, 22325–22336 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. 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).

    Article  CAS  PubMed  Google Scholar 

  190. Hasegawa, E., Takeshige, K., Oishi, T., Murai, Y. & Minakami, S. 1-Methyl-4-phenylpyridinium (MPP+) induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particles. Biochem. Biophys. Res. Commun. 170, 1049–1055 (1990).

    Article  CAS  PubMed  Google Scholar 

  191. Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci. 3, 1301–1306 (2000).

    Article  CAS  PubMed  Google Scholar 

  192. Cocheme, H. M. & Murphy, M. P. Complex I is the major site of mitochondrial superoxide production by paraquat. J. Biol. Chem. 283, 1786–1798 (2008).

    Article  CAS  PubMed  Google Scholar 

  193. Schapira, A. H. et al. Mitochondrial complex I deficiency in Parkinson’s disease. J. Neurochem. 54, 823–827 (1990). This key early paper establishes that electron transport chain complex I is a potential pathological point of convergence in PD, finding that complex I activity is specifically reduced in individuals with PD, relative to control individuals.

    Article  CAS  PubMed  Google Scholar 

  194. Keeney, P. M., Xie, J., Capaldi, R. A. & Bennett, J. P. Jr. Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J. Neurosci. 26, 5256–5264 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Devi, L., Raghavendran, V., Prabhu, B. M., Avadhani, N. G. & Anandatheerthavarada, H. K. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J. Biol. Chem. 283, 9089–9100 (2008). This influential paper highlighted mitochondria as a potential site of α-synuclein pathology, with experiments finding that α-synuclein is imported into mitochondria and that a PD-associated α-synuclein mutant has more extensive import and inhibition of complex I.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Morais, V. A. et al. Parkinson’s disease mutations in PINK1 result in decreased complex I activity and deficient synaptic function. EMBO Mol. Med. 1, 99–111 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Cleeter, M. W. et al. Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage. Neurochem. Int. 62, 1–7 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Vilain, S. et al. The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants. PLoS Genet. 8, e1002456 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Vos, M. et al. Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. Science 336, 1306–1310 (2012).

    Article  CAS  PubMed  Google Scholar 

  200. Bi, F., Li, F., Huang, C. & Zhou, H. Pathogenic mutation in VPS35 impairs its protection against MPP(+) cytotoxicity. Int. J. Biol. Sci. 9, 149–155 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Tang, F. L. et al. VPS35 deficiency or mutation causes dopaminergic neuronal loss by impairing mitochondrial fusion and function. Cell Rep. 12, 1631–1643 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Zhou, L., Wang, W., Hoppel, C., Liu, J. & Zhu, X. Parkinson’s disease-associated pathogenic VPS35 mutation causes complex I deficits. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 2791–2795 (2017).

    Article  CAS  PubMed  Google Scholar 

  203. Gonzalez-Rodriguez, P. et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 599, 650–656 (2021). In this work, mice with dopaminergic neuron-specific knockdown of a complex I component develop l-DOPA-responsive Parkinsonian deficits in learning, behaviour and motor coordination, supporting a central role of complex I impairment in PD pathogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Dryanovski, D. I. et al. Calcium entry and alpha-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons. J. Neurosci. 33, 10154–10164 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Nakamura, K. et al. Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J. Biol. Chem. 286, 20710–20726 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Choi, M. L. et al. Pathological structural conversion of alpha-synuclein at the mitochondria induces neuronal toxicity. Nat. Neurosci. 25, 1134–1148 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Di Maio, R. et al. alpha-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci. Transl. Med. 8, 342ra378 (2016).

    Google Scholar 

  208. Wang, X. et al. LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum. Mol. Genet. 21, 1931–1944 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Wang, W. et al. Parkinson’s disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes. Nat. Med. 22, 54–63 (2016).

    Article  CAS  PubMed  Google Scholar 

  210. Papkovskaia, T. D. et al. G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization. Hum. Mol. Genet. 21, 4201–4213 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Krebiehl, G. et al. Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson’s disease-associated protein DJ-1. PLoS ONE 5, e9367 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Li, G. et al. PTENα regulates mitophagy and maintains mitochondrial quality control. Autophagy 14, 1742–1760 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Wang, L. et al. PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1-parkin-mediated mitophagy. Cell Res. 28, 787–802 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Domanskyi, A. et al. Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson’s disease models. FASEB J. 25, 2898–2910 (2011).

    Article  CAS  PubMed  Google Scholar 

  215. Choi, M. S. et al. Transnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in Parkinson’s disease models. J. Neurosci. 34, 15123–15131 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. McWilliams, T. G. et al. Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab. 27, 439–449.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Yamano, K. & Youle, R. J. PINK1 is degraded through the N-end rule pathway. Autophagy 9, 1758–1769 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Morais, V. A. et al. PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science 344, 203–207 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Mazzulli, J. R., Zunke, F., Isacson, O., Studer, L. & Krainc, D. α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc. Natl Acad. Sci. USA 113, 1931–1936 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Goncalves, S. A. et al. shRNA-based screen identifies endocytic recycling pathway components that act as genetic modifiers of alpha-synuclein aggregation, secretion and toxicity. PLoS Genet. 12, e1005995 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Nim, S. et al. Disrupting the alpha-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease. Nat. Commun. 14, 2150 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Lindersson, E. et al. Proteasomal inhibition by alpha-synuclein filaments and oligomers. J. Biol. Chem. 279, 12924–12934 (2004).

    Article  CAS  PubMed  Google Scholar 

  226. 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).

    Article  CAS  PubMed  Google Scholar 

  227. Xilouri, M., Vogiatzi, T., Vekrellis, K., Park, D. & Stefanis, L. Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS ONE 4, e5515 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Winslow, A. R. et al. α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J. Cell Biol. 190, 1023–1037 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Tanik, S. A., Schultheiss, C. E., Volpicelli-Daley, L. A., Brunden, K. R. & Lee, V. M. Lewy body-like alpha-synuclein aggregates resist degradation and impair macroautophagy. J. Biol. Chem. 288, 15194–15210 (2013). This paper supports autophagy as an important node in the toxicity of α-synuclein, with experiments demonstrating that α-synuclein oligomers are refractory to autophagic degradation and inhibit autophagosome maturation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Crews, L. et al. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS ONE 5, e9313 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  231. Orenstein, S. J. et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat. Neurosci. 16, 394–406 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Sardi, S. P. et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc. Natl Acad. Sci. USA 110, 3537–3542 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Sardi, S. P. et al. Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models. Proc. Natl Acad. Sci. USA 114, 2699–2704 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Mazzulli, J. R. et al. Activation of beta-glucocerebrosidase reduces pathological alpha-synuclein and restores lysosomal function in Parkinson’s patient midbrain neurons. J. Neurosci. 36, 7693–7706 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Miura, E. et al. VPS35 dysfunction impairs lysosomal degradation of alpha-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson’s disease. Neurobiol. Dis. 71, 1–13 (2014).

    Article  CAS  PubMed  Google Scholar 

  236. Tang, F. L. et al. VPS35 in dopamine neurons is required for endosome-to-Golgi retrieval of lamp2a, a receptor of chaperone-mediated autophagy that is critical for alpha-synuclein degradation and prevention of pathogenesis of Parkinson’s disease. J. Neurosci. 35, 10613–10628 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Chen, X. et al. Parkinson’s disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration. Proc. Natl Acad. Sci. USA 116, 5765–5774 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Mir, R. et al. The Parkinson’s disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. Biochem. J. 475, 1861–1883 (2018). The findings of this paper offer a link between VPS35 and LRRK2 in PD pathogenesis, showing that LRRK2 activity is increased in cells with the VPS35 D620N mutation in a manner that can be rescued by VPS35 suppression.

    Article  CAS  PubMed  Google Scholar 

  239. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).

    Article  CAS  PubMed  Google Scholar 

  240. St-Pierre, J. et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127, 397–408 (2006).

    Article  CAS  PubMed  Google Scholar 

  241. Ciron, C. et al. PGC-1alpha activity in nigral dopamine neurons determines vulnerability to alpha-synuclein. Acta Neuropathol. Commun. 3, 16 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  242. Yang, L. et al. Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. PLoS ONE 4, e5757 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  243. Zheng, B. et al. PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci. Transl. Med. 2, 52ra73 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  244. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Decressac, M. et al. TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. Proc. Natl Acad. Sci. USA 110, E1817–E1826 (2013). This paper provides another link between α-synuclein pathology and autophagy, showing that α-synuclein toxicity is reduced by overexpression or activation of TFEB, a transcription factor that is a master regulator of lysosome biogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Settembre, C. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15, 647–658 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Nezich, C. L., Wang, C., Fogel, A. I. & Youle, R. J. MiT/TFE transcription factors are activated during mitophagy downstream of parkin and Atg5. J. Cell Biol. 210, 435–450 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Bonello, F. et al. LRRK2 impairs PINK1/parkin-dependent mitophagy via its kinase activity: pathologic insights into Parkinson’s disease. Hum. Mol. Genet. 28, 1645–1660 (2019).

    Article  CAS  PubMed  Google Scholar 

  249. Cooper, O. et al. Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease. Sci. Transl. Med. 4, 141ra190 (2012).

    Article  Google Scholar 

  250. Stafa, K. et al. Functional interaction of Parkinson’s disease-associated LRRK2 with members of the dynamin GTPase superfamily. Hum. Mol. Genet. 23, 2055–2077 (2014).

    Article  CAS  PubMed  Google Scholar 

  251. Hsieh, C. H. et al. Functional impairment in Miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell 19, 709–724 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Wauters, F. et al. LRRK2 mutations impair depolarization-induced mitophagy through inhibition of mitochondrial accumulation of RAB10. Autophagy 16, 203–222 (2020).

    Article  CAS  PubMed  Google Scholar 

  253. Ma, K. Y., Fokkens, M. R., Reggiori, F., Mari, M. & Verbeek, D. S. Parkinson’s disease-associated VPS35 mutant reduces mitochondrial membrane potential and impairs PINK1/parkin-mediated mitophagy. Transl. Neurodegener. 10, 19 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Hanss, Z. et al. Mitochondrial and clearance impairment in p.D620N VPS35 patient-derived neurons. Mov. Disord. 36, 704–715 (2021).

    Article  CAS  PubMed  Google Scholar 

  255. Gusdon, A. M., Zhu, J., Van Houten, B. & Chu, C. T. ATP13A2 regulates mitochondrial bioenergetics through macroautophagy. Neurobiol. Dis. 45, 962–972 (2012).

    Article  CAS  PubMed  Google Scholar 

  256. Osellame, L. D. et al. Mitochondria and quality control defects in a mouse model of Gaucher disease — links to Parkinson’s disease. Cell Metab. 17, 941–953 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Baden, P. et al. Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism. Nat. Commun. 14, 1930 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Hancock-Cerutti, W. et al. ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling. J. Cell Biol. 221, e202106046 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  259. Schröder, L. F. et al. VPS13C regulates phospho-Rab10-mediated lysosomal function in human dopaminergic neurons. J. Cell Biol. 223, e202304042 (2024).

    Article  Google Scholar 

  260. Demers-Lamarche, J. et al. Loss of mitochondrial function impairs lysosomes. J. Biol. Chem. 291, 10263–10276 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Guerra, F. et al. Synergistic effect of mitochondrial and lysosomal dysfunction in Parkinson’s disease. Cells 8, 452 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Sugiura, A., McLelland, G. L., Fon, E. A. & McBride, H. M. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. EMBO J. 33, 2142–2156 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Konig, T. et al. MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control. Nat. Cell Biol. 23, 1271–1286 (2021).

    Article  CAS  PubMed  Google Scholar 

  264. McLelland, G. L., Soubannier, V., Chen, C. X., McBride, H. M. & Fon, E. A. Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J. 33, 282–295 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. Matheoud, D. et al. Parkinson’s disease-related proteins PINK1 and parkin repress mitochondrial antigen presentation. Cell 166, 314–327 (2016).

    Article  CAS  PubMed  Google Scholar 

  266. Braschi, E. et al. Vps35 mediates vesicle transport between the mitochondria and peroxisomes. Curr. Biol. 20, 1310–1315 (2010).

    Article  CAS  PubMed  Google Scholar 

  267. Kim, S., Coukos, R., Gao, F. & Krainc, D. Dysregulation of organelle membrane contact sites in neurological diseases. Neuron 110, 2386–2408 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Wong, Y. C., Ysselstein, D. & Krainc, D. Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature 554, 382–386 (2018). The demonstration in this paper that mitochondria and lysosomes engage in dynamic contacts that are independent of mitophagy suggests a possible functional node of convergence for pathogenic PD proteins that operate primarily at either of these organelles.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Yamano, K., Fogel, A. I., Wang, C., van der Bliek, A. M. & Youle, R. J. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. eLife 3, e01612 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  270. Heo, J. M. et al. RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway. Sci. Adv. 4, eaav0443 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Yamano, K. et al. Endosomal Rab cycles regulate parkin-mediated mitophagy. eLife 7, e31326 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  272. Kim, S., Wong, Y. C., Gao, F. & Krainc, D. Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s disease. Nat. Commun. 12, 1807 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Song, P., Trajkovic, K., Tsunemi, T. & Krainc, D. Parkin modulates endosomal organization and function of the endo-lysosomal pathway. J. Neurosci. 36, 2425–2437 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Peng, W., Schroder, L. F., Song, P., Wong, Y. C. & Krainc, D. Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson’s disease. Sci. Adv. 9, eadh3347 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Jimenez-Orgaz, A. et al. Control of RAB7 activity and localization through the retromer-TBC1D5 complex enables RAB7-dependent mitophagy. EMBO J. 37, 235–254 (2018).

    Article  CAS  PubMed  Google Scholar 

  276. Cioni, J. M. et al. Late endosomes act as mRNA translation platforms and sustain mitochondria in axons. Cell 176, 56–72.e15 (2019). This paper demonstrates that axonal interactions between late endosomes and mitochondria are found to support the local translation of mitochondrial proteins, expanding the functional role of mitochondria–lysosome contacts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Hughes, A. L. & Gottschling, D. E. An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature 492, 261–265 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Guardia-Laguarta, C. et al. α-Synuclein is localized to mitochondria-associated ER membranes. J. Neurosci. 34, 249–259 (2014). The finding of this study that α-synuclein localizes to ER–mitochondria contacts, where it induces mitochondrial fragmentation, suggests a potential mechanistic connection between mitochondrial and ER stresses produced by pathological α-synuclein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Celardo, I. et al. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s disease. Cell Death Dis. 7, e2271 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. McLelland, G. L. et al. Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy. eLife 7, e32866 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  281. Hamasaki, M. et al. Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389–393 (2013).

    Article  CAS  PubMed  Google Scholar 

  282. Toyofuku, T., Okamoto, Y., Ishikawa, T., Sasawatari, S. & Kumanogoh, A. LRRK2 regulates endoplasmic reticulum-mitochondrial tethering through the PERK-mediated ubiquitination pathway. EMBO J. 39, e100875 (2020).

    Article  CAS  PubMed  Google Scholar 

  283. Bonet-Ponce, L. & Cookson, M. R. The endoplasmic reticulum contributes to lysosomal tubulation/sorting driven by LRRK2. Mol. Biol. Cell 33, ar124 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Liu, Y. et al. DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1. Proc. Natl Acad. Sci. USA 116, 25322–25328 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Paillusson, S. et al. α-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production. Acta Neuropathol. 134, 129–149 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Parrado-Fernandez, C. et al. Reduction of PINK1 or DJ-1 impair mitochondrial motility in neurites and alter ER-mitochondria contacts. J. Cell Mol. Med. 22, 5439–5449 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Williams, E. T. et al. Parkin mediates the ubiquitination of VPS35 and modulates retromer-dependent endosomal sorting. Hum. Mol. Genet. 27, 3189–3205 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Cao, M., Milosevic, I., Giovedi, S. & De Camilli, P. Upregulation of parkin in endophilin mutant mice. J. Neurosci. 34, 16544–16549 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  289. Sanyal, A., Novis, H. S., Gasser, E., Lin, S. & LaVoie, M. J. LRRK2 kinase inhibition rescues deficits in lysosome function due to heterozygous GBA1 expression in human iPSC-derived neurons. Front. Neurosci. 14, 442 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  290. Dagda, R. K. et al. Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through protein kinase A. J. Neurochem. 128, 864–877 (2014).

    Article  CAS  PubMed  Google Scholar 

  291. Ko, H. S. et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc. Natl Acad. Sci. USA 107, 16691–16696 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Shin, J. H. et al. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell 144, 689–702 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Lee, Y. et al. PINK1 primes parkin-mediated ubiquitination of PARIS in dopaminergic neuronal survival. Cell Rep. 18, 918–932 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Kostic, M. et al. PKA phosphorylation of NCLX reverses mitochondrial calcium overload and depolarization, promoting survival of PINK1-deficient dopaminergic neurons. Cell Rep. 13, 376–386 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Ham, S. J. et al. PINK1 and parkin regulate IP(3)R-mediated ER calcium release. Nat. Commun. 14, 5202 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Betzer, C. et al. Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation. EMBO Rep. 19, e44617 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  297. Schondorf, D. C. et al. iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis. Nat. Commun. 5, 4028 (2014).

    Article  PubMed  Google Scholar 

  298. Medina, D. L. et al. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat. Cell Biol. 17, 288–299 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  299. Zhang, X. et al. MCOLN1 is a ROS sensor in lysosomes that regulates autophagy. Nat. Commun. 7, 12109 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. Pollmanns, M. R. et al. Activated endolysosomal cation channel TRPML1 facilitates maturation of alpha-synuclein-containing autophagosomes. Front. Cell Neurosci. 16, 861202 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Bademosi, A. T. et al. EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation. Neuron 111, 1402–1422.13 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Lautenschlager, J. et al. C-Terminal calcium binding of alpha-synuclein modulates synaptic vesicle interaction. Nat. Commun. 9, 712 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank fellow members of the Krainc laboratory for the discussion and feedback related to the topics covered and the preparation of the manuscript.

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  1. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Robert Coukos & Dimitri Krainc

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Correspondence to Dimitri Krainc.

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D.K. is the Founder and Scientific Advisory Board Chair of Vanqua Bio, serves on the scientific advisory boards of The Silverstein Foundation, Intellia Therapeutics and AcureX Therapeutics, and is a Venture Partner at OrbiMed. The authors declare that they have no other competing interests.

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Glossary

Chaperone-mediated autophagy

(CMA). A form of protein degradation in which client proteins, recognized by chaperones based on the presence of a CMA motif, are directly imported into lysosomes through the receptor LAMP2. It is possible that CMA may be highly cell type or context specific.

Chaperones

Proteins that assist in the folding or unfolding of other client proteins.

Electron transport chain

A series of complexes in the inner mitochondrial membrane that use the energy from redox reactions involving electron transfer to establish a proton gradient between the mitochondrial matrix and intermembrane space. ATP synthase harvests the electrochemical potential of this gradient to regenerate ATP.

Endosomes

Small membranous vesicles that mediate protein and lipid trafficking, recycling and sorting between other compartments of the endomembrane system, including the plasma membrane, trans-Golgi network and lysosomes.

Exosomes

One of a category of small membranous vesicles that form within multivesicular bodies and are released into the extracellular space upon fusion of the multivesicular body with the plasma membrane.

Lewy body

A dense inclusion of α-synuclein fibrils, ubiquitin, trapped organelles and other cellular materials that is a pathological hallmark in dopaminergic neurons in many models and clinical presentations of Parkinson disease.

Lysosome

An acidic, membrane-bound compartment of the endomembrane system that contains a suite of proteases and other degradative enzymes. Lysosomes also have nutrient-sensing and signalling functions.

Macroautophagy

Also referred to simply as autophagy. A process by which bulk cytosolic content, including organelles, are enveloped within double-membraned phagophores, which mature into autophagosomes and then fuse with lysosomes to mediate the degradation of the enveloped content.

Mitophagy

A type of autophagy specific to mitochondria. Mitophagy can be initiated by the kinase activity of PINK1 and the ubiquitin ligase activity of parkin in response to various forms of mitochondrial stress or damage.

Multivesicular body

(MVB). A membrane-bound compartment that contains internal vesicles generated by the inward budding of small vesicles from the outer, limiting membrane into the lumen of the compartment.

Oxidative stress

Cellular damage that accrues through the generation of reactive oxygen species in excess of the antioxidant capacity of a cell.

Phagophore

A membranous sheet that forms during the initial stages of autophagy. The phagophore folds around and sequesters cargo targeted for degradation before enclosing to form an autophagosome.

Proteasomes

Cytosolic, megadalton-scale protease complexes, generally involved in the degradation of ubiquitinated proteins.

Retromer complex

A protein complex consisting of VPS35, VPS39 and either VPS26A or VPS26B, which functions in sorting and retrograde trafficking of transmembrane proteins from endosomes to the trans-Golgi network or recycling from endosomes to the plasma membrane.

Sporadic PD

Cases of Parkinson disease (PD) without an attributable genetic cause. Also called idiopathic PD.

Synaptic vesicle recycling

The process by which the membrane and protein components of synaptic vesicles are recovered from the plasma membrane after neurotransmitter release (via endocytosis) and used to regenerate new synaptic vesicles.

Trans-Golgi network

A membrane compartment downstream of the endoplasmic reticulum in the secretory pathway, which mediates the initial processing and sorting of proteins that will be either secreted or retained within the lumen of other membrane compartments.

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Coukos, R., Krainc, D. Key genes and convergent pathogenic mechanisms in Parkinson disease. Nat. Rev. Neurosci. (2024). https://doi.org/10.1038/s41583-024-00812-2

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