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.

What is the role of protein aggregation in neurodegeneration?

Abstract

Neurodegenerative diseases typically involve deposits of inclusion bodies that contain abnormal aggregated proteins. Therefore, it has been suggested that protein aggregation is pathogenic. However, several lines of evidence indicate that inclusion bodies are not the main cause of toxicity, and probably represent a cellular protective response. Aggregation is a complex multi-step process of protein conformational change and accretion. The early species in this process might be most toxic, perhaps through the exposure of buried moieties such as main chain NH and CO groups that could serve as hydrogen bond donors or acceptors in abnormal interactions with other cellular proteins. This model implies that the pathogenesis of diverse neurodegenerative diseases arises by common mechanisms, and might yield common therapeutic targets.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Intranuclear, cytoplasmic and extracellular aggregates and inclusion bodies visualized by light microscopy.
Figure 2: Cellular defence mechanisms against aggregated abnormal proteins.
Figure 3: Potential pathways for formation of inclusion bodies and other protein aggregates.

References

  1. 1

    DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2

    Bates, G. Huntingtin aggregation and toxicity in Huntington's disease. Lancet 361, 1642–1644 (2003).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Selkoe, D. J. Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nature Cell Biol. 6, 1054–1061 (2004).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Ross, C. A. & Poirier, M. A. Protein aggregation and neurodegenerative disease. Nature Med. 10, S10–S17 (2004).

    PubMed  Article  CAS  Google Scholar 

  5. 5

    Cohen, F. E. & Kelly, J. W. Therapeutic approaches to protein-misfolding diseases. Nature 426, 905–909 (2003).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Buxbaum, J. N. Diseases of protein conformation: what do in vitro experiments tell us about in vivo diseases? Trends Biochem. Sci. 28, 585–592 (2003).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Dobson, C. M. Protein folding and misfolding. Nature 426, 884–890 (2003).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Stefani, M. & Dobson, C. M. Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J. Mol. Med. 81, 678–699 (2003).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Dawson, T. M. & Dawson, V. L. Molecular pathways of neurodegeneration in Parkinson's disease. Science 302, 819–822 (2003).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Bucciantini, M. et al. Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J. Biol. Chem. 279, 31374–31382 (2004).

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Makin, O. S. & Serpell, L. C. X-ray diffraction studies of amyloid structure. Methods Mol. Biol. 299, 67–80 (2005).

    CAS  PubMed  Google Scholar 

  12. 12

    Ross, C. A. & Margolis, R. L. Neurogenetics: insights into degenerative diseases and approaches to schizophrenia. Clin. Neurosci. Res. (in the press).

  13. 13

    Eanes, E. D. & Glenner, G. G. X-ray diffraction studies on amyloid filaments. J. Histochem. Cytochem. 16, 673–677 (1968).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Sunde, M. & Blake, C. C. From the globular to the fibrous state: protein structure and structural conversion in amyloid formation. Q. Rev. Biophys. 31, 1–39 (1998).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Terry, R. D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Tompkins, M. M. & Hill, W. D. Contribution of somal Lewy bodies to neuronal death. Brain Res. 775, 24–29 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Gutekunst, C. A. et al. Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J. Neurosci. 19, 2522–2534 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18

    Kuemmerle, S. et al. Huntington aggregates may not predict neuronal death in Huntington's disease. Ann. Neurol. 46, 842–849 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M. E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R. & Finkbeiner, S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805–810 (2004).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Stefanis, L., Larsen, K. E., Rideout, H. J., Sulzer, D. & Greene, L. A. Expression of A53T mutant but not wild-type a-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J. Neurosci. 21, 9549–9560 (2001).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Tanaka, Y. et al. Inducible expression of mutant α-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum. Mol. Genet. 10, 919–926 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    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  Article  Google Scholar 

  24. 24

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

    CAS  Article  PubMed  Google Scholar 

  25. 25

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

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Warrick, J. M. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nature Genet. 23, 425–428 (1999).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Muchowski, P. J. & Wacker, J. L. Modulation of neurodegeneration by molecular chaperones. Nature Rev. Neurosci. 6, 11–22 (2005).

    CAS  Article  Google Scholar 

  28. 28

    Hansson, O. et al. Overexpression of heat shock protein 70 in R6/2 Huntington's disease mice has only modest effects on disease progression. Brain Res. 970, 47–57 (2003).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Cummings, C. J. et al. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum. Mol. Genet. 10, 1511–1518 (2001).

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Ross, C. A. & Pickart, C. The ubiquitin–proteasome pathway in Parkinson's and other neurodegenerative diseases. Trends Cell Biol. 14, 703–711 (2004).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Berke, S. J. & Paulson, H. L. Protein aggregation and the ubiquitin–proteasome pathway: gaining the UPPer hand on neurodegeneration. Curr. Opin. Genet. Dev. 13, 253–261 (2003).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Majeski, A. E. & Dice, J. F. Mechanisms of chaperone-mediated autophagy. Int. J. Biochem. Cell Biol. 36, 2435–2444 (2004).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Massey, A., Kiffin, R. & Cuervo, A. M. Pathophysiology of chaperone-mediated autophagy. Int. J. Biochem. Cell Biol. 36, 2420–2434 (2004).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Kiffin, R., Christian, C., Knecht, E. & Cuervo, A. M. Activation of chaperone-mediated autophagy during oxidative stress. Mol. Biol. Cell 15, 4829–4840 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Ravikumar, B. et al. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nature Genet. 37, 771–776 (2005).

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Johnston, J. A., Ward, C. L. & Kopito, R. R. Aggresomes: a cellular response to misfolded proteins. J. Cell Biol. 143, 1883–1898 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Olanow, C. W., Perl, D. P., DeMartino, G. N. & McNaught, K. S. Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol. 3, 496–503 (2004).

    PubMed  Article  Google Scholar 

  39. 39

    Iwata, A. et al. Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc. Natl Acad. Sci. USA (in the press).

  40. 40

    Levine, B. Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120, 159–162 (2005).

    CAS  PubMed  Google Scholar 

  41. 41

    Rideout, H. J., Lang-Rollin, I. & Stefanis, L. Involvement of macroautophagy in the dissolution of neuronal inclusions. Int. J. Biochem. Cell Biol. 36, 2551–2562 (2004).

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Fortun, J., Dunn, W. A., Joy, S., Li, J. & Notterpek, L. Emerging role for autophagy in the removal of aggresomes in Schwann cells. J. Neurosci. 23, 10672–10680 (2003).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Qin, Z. H. et al. Autophagy regulates the processing of amino terminal huntingtin fragments. Hum. Mol. Genet. 12, 3231–3244 (2003).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    McGeer, P. L. & McGeer, E. G. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res. Rev. 21, 195–218 (1995).

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Yamamoto, A., Lucas, J. J. & Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57–66 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46

    Martin-Aparicio, E. et al. Proteasomal-dependent aggregate reversal and absence of cell death in a conditional mouse model of Huntington's disease. J. Neurosci. 21, 8772–8781 (2001).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    O'Nuallain, B. & Wetzel, R. Conformational Abs recognizing a generic amyloid fibril epitope. Proc. Natl Acad. Sci. USA 99, 1485–1490 (2002).

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Tanaka, M., Chien, P., Naber, N., Cooke, R. & Weissman, J. S. Conformational variations in an infectious protein determine prion strain differences. Nature 428, 323–328 (2004).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Weissmann, C. Birth of a prion: spontaneous generation revisited. Cell 122, 165–168 (2005).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Serio, T. R. et al. Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science 289, 1317–1321 (2000).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Collins, S. R., Douglass, A., Vale, R. D. & Weissman, J. S. Mechanism of prion propagation: amyloid growth occurs by monomer addition. PLoS Biol. 2, e321 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53

    Williams, A. D. et al. Structural properties of Ab protofibrils stabilized by a small molecule. Proc. Natl Acad. Sci. USA (in the press).

  54. 54

    McLean, C. A. et al. Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 46, 860–866 (1999).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Lue, L. F. et al. Soluble amyloid-β peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am. J. Pathol. 155, 853–862 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Klein, W. L., Krafft, G. A. & Finch, C. E. Targeting small A-β oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 24, 219–224 (2001).

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Walsh, D. M. et al. Amyloid β-protein fibrillogenesis. structure and biological activity of protofibrillar intermediates. J. Biol. Chem. 274, 25945–25952 (1999).

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Chromy, B. A. et al. Self-assembly of A-β1–42 into globular neurotoxins. Biochemistry 42, 12749–12760 (2003).

    CAS  PubMed  Article  Google Scholar 

  59. 59

    Gong, Y. et al. Alzheimer's disease-affected brain: presence of oligomeric Ab ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc. Natl Acad. Sci. USA 100, 10417–10422 (2003).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Bitan, G. et al. Amyloid β-protein (Ab) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways. Proc. Natl Acad. Sci. USA 100, 330–335 (2003).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Walsh, D. M. et al. Naturally secreted oligomers of amyloid b protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Klyubin, I. et al. Amyloid β protein immunotherapy neutralizes Ab oligomers that disrupt synaptic plasticity in vivo. Nature Med. 11, 556–561 (2005).

    CAS  PubMed  Article  Google Scholar 

  63. 63

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

    Poirier, M. A. et al. Huntingtin spheroids and protofibrils as precursors in polyglutamine fibrilization. J. Biol. Chem. 277, 41032–41037 (2002).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Wacker, J. L., Zareie, M. H., Fong, H., Sarikaya, M. & Muchowski, P. J. Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nature Struct. Mol. Biol. 11, 1215–1222 (2004).

    CAS  Article  Google Scholar 

  66. 66

    Chen, S., Ferrone, F. A. & Wetzel, R. Huntington's disease age-of-onset linked to polyglutamine aggregation nucleation. Proc. Natl Acad. Sci. USA 99, 11884–11889 (2002).

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Thakur, A. K. & Wetzel, R. Mutational analysis of the structural organization of polyglutamine aggregates. Proc. Natl Acad. Sci. USA 99, 17014–17019 (2002).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Poirier, M. A., Jiang, H. & Ross, C. A. A structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure. Hum. Mol. Genet. 14, 765–774 (2005).

    CAS  PubMed  Article  Google Scholar 

  69. 69

    Selkoe, D. J. Alzheimer disease: mechanistic understanding predicts novel therapies. Ann. Intern. Med. 140, 627–638 (2004).

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Bence, N. F., Sampat, R. M. & Kopito, R. R. Impairment of the ubiquitin–proteasome system by protein aggregation. Science 292, 1552–1555 (2001).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Venkatraman, P., Wetzel, R., Tanaka, M., Nukina, N. & Goldberg, A. L. Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol. Cell 14, 95–104 (2004).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Verhoef, L. G., Lindsten, K., Masucci, M. G. & Dantuma, N. P. Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum. Mol. Genet. 11, 2689–2700 (2002).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Jana, N. R., Zemskov, E. A., Wang, G. & Nukina, N. Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum. Mol. Genet. 10, 1049–1059 (2001).

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Bennett, E. J., Bence, N. F., Jayakumar, R. & Kopito, R. R. Global impairment of the ubiquitin–proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol. Cell 17, 351–365 (2005).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Bowman, A. B., Yoo, S. Y., Dantuma, N. P. & Zoghbi, H. Y. Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin–proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum. Mol. Genet. 14, 679–691 (2005).

    CAS  PubMed  Article  Google Scholar 

  76. 76

    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  Article  Google Scholar 

  77. 77

    McCampbell, A. et al. CREB-binding protein sequestration by expanded polyglutamine. Hum. Mol. Genet. 9, 2197–2202 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78

    Preisinger, E., Jordan, B. M., Kazantsev, A. & Housman, D. Evidence for a recruitment and sequestration mechanism in Huntington's disease. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 354, 1029–1034 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    Kazantsev, A., Preisinger, E., Dranovsky, A., Goldgaber, D. & Housman, D. Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc. Natl Acad. Sci. USA 96, 11404–11409 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80

    Nucifora, F. C., Jr. et al. Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science 291, 2423–2428 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    Chen, S., Berthelier, V., Yang, W. & Wetzel, R. Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J. Mol. Biol. 311, 173–182 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82

    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  Article  Google Scholar 

  83. 83

    Ross, C. A. et al. Huntington disease and the related disorder, dentatorubral-pallidoluysian atrophy (DRPLA). Medicine (Baltimore) 76, 305–338 (1997).

    CAS  Article  Google Scholar 

  84. 84

    Wanker, E. E. Protein aggregation and pathogenesis of Huntington's disease: mechanisms and correlations. Biol. Chem. 381, 937–942 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85

    Hardy, J. Toward Alzheimer therapies based on genetic knowledge. Annu. Rev. Med. 55, 15–25 (2004).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Wood, J. D., Beaujeux, T. P. & Shaw, P. J. Protein aggregation in motor neurone disorders. Neuropathol. Appl. Neurobiol. 29, 529–545 (2003).

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Chien, P., Weissman, J. S. & DePace, A. H. Emerging principles of conformation-based prion inheritance. Annu. Rev. Biochem. 73, 617–656 (2004).

    CAS  PubMed  Article  Google Scholar 

  88. 88

    Revesz, T. et al. Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J. Neuropathol. Exp. Neurol. 62, 885–898 (2003).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Hedera, P. & Turner, R. S. Inherited dementias. Neurol. Clin. 20, 779–808 (2002).

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

C.A.R. and M.A.P. and the Huntington's Disease Center are supported by the National Institute of Neurological Disease and Stroke, the National Institute of Ageing, the High-Q Foundation, the Huntington's Disease Society of America and the Hereditary Disease Foundation. We thank R. Wetzel for detailed reading and comments on the manuscript and sharing data prior to publication, and C. Dobson, D. Rubinsztein, P. Lansbury, R. Kopito, S. Radford, E. Wanker, J. Kelly, M. Amzel and L. Ellerby for comments, discussions or the sharing of data. We also thank the participants of the I2CAM meeting on protein aggregation in Lausanne, Switzerland, July 2005, organized by H. Lashuel, for comments and suggestions, and the participants of the High Q workshop on aggregation organized by A. Tobin and E. Signer in New York, April 2005, for discussion.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

AD

ALS

familial British dementia

familial Danish dementia

frontotemporal dementia

HD

PD

progressive supranuclear palsy

Swiss-Prot

α-synuclein

FURTHER INFORMATION

Christopher Ross's laboratory

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ross, C., Poirier, M. What is the role of protein aggregation in neurodegeneration?. Nat Rev Mol Cell Biol 6, 891–898 (2005). https://doi.org/10.1038/nrm1742

Download citation

Further reading

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