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.
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DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).
Bates, G. Huntingtin aggregation and toxicity in Huntington's disease. Lancet 361, 1642–1644 (2003).
Selkoe, D. J. Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nature Cell Biol. 6, 1054–1061 (2004).
Ross, C. A. & Poirier, M. A. Protein aggregation and neurodegenerative disease. Nature Med. 10, S10–S17 (2004).
Cohen, F. E. & Kelly, J. W. Therapeutic approaches to protein-misfolding diseases. Nature 426, 905–909 (2003).
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).
Dobson, C. M. Protein folding and misfolding. Nature 426, 884–890 (2003).
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).
Dawson, T. M. & Dawson, V. L. Molecular pathways of neurodegeneration in Parkinson's disease. Science 302, 819–822 (2003).
Bucciantini, M. et al. Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J. Biol. Chem. 279, 31374–31382 (2004).
Makin, O. S. & Serpell, L. C. X-ray diffraction studies of amyloid structure. Methods Mol. Biol. 299, 67–80 (2005).
Ross, C. A. & Margolis, R. L. Neurogenetics: insights into degenerative diseases and approaches to schizophrenia. Clin. Neurosci. Res. (in the press).
Eanes, E. D. & Glenner, G. G. X-ray diffraction studies on amyloid filaments. J. Histochem. Cytochem. 16, 673–677 (1968).
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).
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).
Tompkins, M. M. & Hill, W. D. Contribution of somal Lewy bodies to neuronal death. Brain Res. 775, 24–29 (1997).
Gutekunst, C. A. et al. Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J. Neurosci. 19, 2522–2534 (1999).
Kuemmerle, S. et al. Huntington aggregates may not predict neuronal death in Huntington's disease. Ann. Neurol. 46, 842–849 (1999).
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).
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).
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).
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).
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).
Engelender, S. et al. Synphilin-1 associates with a-synuclein and promotes the formation of cytosolic inclusions. Nature Genet. 22, 110–114 (1999).
Tanaka, M. et al. Aggresomes formed by α-synuclein and synphilin-1 are cytoprotective. J. Biol. Chem. 279, 4625–4631 (2004).
Warrick, J. M. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nature Genet. 23, 425–428 (1999).
Muchowski, P. J. & Wacker, J. L. Modulation of neurodegeneration by molecular chaperones. Nature Rev. Neurosci. 6, 11–22 (2005).
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).
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).
Ross, C. A. & Pickart, C. The ubiquitin–proteasome pathway in Parkinson's and other neurodegenerative diseases. Trends Cell Biol. 14, 703–711 (2004).
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).
Majeski, A. E. & Dice, J. F. Mechanisms of chaperone-mediated autophagy. Int. J. Biochem. Cell Biol. 36, 2435–2444 (2004).
Massey, A., Kiffin, R. & Cuervo, A. M. Pathophysiology of chaperone-mediated autophagy. Int. J. Biochem. Cell Biol. 36, 2420–2434 (2004).
Kiffin, R., Christian, C., Knecht, E. & Cuervo, A. M. Activation of chaperone-mediated autophagy during oxidative stress. Mol. Biol. Cell 15, 4829–4840 (2004).
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).
Ravikumar, B. et al. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nature Genet. 37, 771–776 (2005).
Johnston, J. A., Ward, C. L. & Kopito, R. R. Aggresomes: a cellular response to misfolded proteins. J. Cell Biol. 143, 1883–1898 (1998).
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).
Iwata, A. et al. Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc. Natl Acad. Sci. USA (in the press).
Levine, B. Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120, 159–162 (2005).
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).
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).
Qin, Z. H. et al. Autophagy regulates the processing of amino terminal huntingtin fragments. Hum. Mol. Genet. 12, 3231–3244 (2003).
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).
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).
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).
O'Nuallain, B. & Wetzel, R. Conformational Abs recognizing a generic amyloid fibril epitope. Proc. Natl Acad. Sci. USA 99, 1485–1490 (2002).
Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003).
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).
Weissmann, C. Birth of a prion: spontaneous generation revisited. Cell 122, 165–168 (2005).
Serio, T. R. et al. Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science 289, 1317–1321 (2000).
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).
Williams, A. D. et al. Structural properties of Ab protofibrils stabilized by a small molecule. Proc. Natl Acad. Sci. USA (in the press).
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).
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).
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).
Walsh, D. M. et al. Amyloid β-protein fibrillogenesis. structure and biological activity of protofibrillar intermediates. J. Biol. Chem. 274, 25945–25952 (1999).
Chromy, B. A. et al. Self-assembly of A-β1–42 into globular neurotoxins. Biochemistry 42, 12749–12760 (2003).
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).
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).
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).
Klyubin, I. et al. Amyloid β protein immunotherapy neutralizes Ab oligomers that disrupt synaptic plasticity in vivo. Nature Med. 11, 556–561 (2005).
Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T. & Lansbury, P. T. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291 (2002).
Poirier, M. A. et al. Huntingtin spheroids and protofibrils as precursors in polyglutamine fibrilization. J. Biol. Chem. 277, 41032–41037 (2002).
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).
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).
Thakur, A. K. & Wetzel, R. Mutational analysis of the structural organization of polyglutamine aggregates. Proc. Natl Acad. Sci. USA 99, 17014–17019 (2002).
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).
Selkoe, D. J. Alzheimer disease: mechanistic understanding predicts novel therapies. Ann. Intern. Med. 140, 627–638 (2004).
Bence, N. F., Sampat, R. M. & Kopito, R. R. Impairment of the ubiquitin–proteasome system by protein aggregation. Science 292, 1552–1555 (2001).
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).
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).
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).
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).
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).
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).
McCampbell, A. et al. CREB-binding protein sequestration by expanded polyglutamine. Hum. Mol. Genet. 9, 2197–2202 (2000).
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).
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).
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).
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).
Quist, A. et al. Amyloid ion channels: A common structural link for protein-misfolding disease. Proc. Natl Acad. Sci. USA 102, 10427–10432 (2005).
Ross, C. A. et al. Huntington disease and the related disorder, dentatorubral-pallidoluysian atrophy (DRPLA). Medicine (Baltimore) 76, 305–338 (1997).
Wanker, E. E. Protein aggregation and pathogenesis of Huntington's disease: mechanisms and correlations. Biol. Chem. 381, 937–942 (2000).
Hardy, J. Toward Alzheimer therapies based on genetic knowledge. Annu. Rev. Med. 55, 15–25 (2004).
Wood, J. D., Beaujeux, T. P. & Shaw, P. J. Protein aggregation in motor neurone disorders. Neuropathol. Appl. Neurobiol. 29, 529–545 (2003).
Chien, P., Weissman, J. S. & DePace, A. H. Emerging principles of conformation-based prion inheritance. Annu. Rev. Biochem. 73, 617–656 (2004).
Revesz, T. et al. Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J. Neuropathol. Exp. Neurol. 62, 885–898 (2003).
Hedera, P. & Turner, R. S. Inherited dementias. Neurol. Clin. 20, 779–808 (2002).
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.
The authors declare no competing financial interests.
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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
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