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Protein aggregation and neurodegenerative disease

Nature Medicine volume 10, pages S10S17 (2004) | Download Citation

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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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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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  1. Christopher A. Ross is in the Division of Neurobiology, Department of Psychiatry, and Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Ross Research Building, Room 618, 720 Rutland Avenue, Baltimore, Maryland 21205, USA. caross@jhu.edu

    • Christopher A Ross
  2. Michelle A. Poirier is in the Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Ross Research Building, Room 618, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.

    • Michelle A Poirier

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