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Protein aggregation and neurodegenerative disease

Abstract

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation. The aggregates usually consist of fibers containing misfolded protein with a β-sheet conformation, termed amyloid. There is partial but not perfect overlap among the cells in which abnormal proteins are deposited and the cells that degenerate. The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves. For several diseases, genetic variants assist in explaining the pathogenesis of the more common sporadic forms and developing mouse and other models. There is now increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity. These are leading to approaches toward rational therapeutics.

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Figure 1: Characteristic neurodegenerative disease neuropathological lesions involve deposition of abnormal proteins, which can be intranuclear, cytoplasmic or extracellular.
Figure 2: β-sheet, β-turn models for expanded polyglutamine and Aβ amyloid suggest commonalities in amyloid structure in different neurodegenerative diseases.
Figure 3: Flowchart for therapeutic intervention in a hypothetical several-step pathway of protein aggregation.

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Acknowledgements

Supported by NINDS NS16375, NS38144, NS34172, NS38377, the Huntington's Disease Society of America, the Hereditary Disease Foundation, and the High-Q Foundation. We thank the anonymous reviewers for their comments and suggestions. JCT is supported by NINDS NS16375, NS38377 and NIA AG05146.

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Ross, C., Poirier, M. Protein aggregation and neurodegenerative disease. Nat Med 10, S10–S17 (2004). https://doi.org/10.1038/nm1066

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