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Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs

Nature Medicine volume 10, pages 1055–1063 (2004)Cite this article

Abstract

A wide variety of neurodegenerative diseases are characterized by the accumulation of intracellular or extracellular protein aggregates. More recently, the genetic identification of mutations in familial counterparts to the sporadic disorders, leading to the development of in vitro and in vivo model systems, has provided insights into disease pathogenesis. The effect of many of these mutations is the abnormal processing of misfolded proteins that overwhelms the quality-control systems of the cell, resulting in the deposition of protein aggregates in the nucleus, cytosol and/or extracellular space. Further understanding of mechanisms regulating protein processing and aggregation, as well as of the toxic effects of misfolded neurodegenerative disease proteins, will facilitate development of rationally designed therapies to treat and prevent these disorders.

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Figure 1: Model of protein misfolding and fibrillization, leading to the deposition of aggregated protein in the nucleus, cytoplasm and extracellular space.

Deborah Maizels

Figure 2: Protein aggregates in neurodegenerative disease.
Figure 3

Deborah Maizels

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Acknowledgements

We are indebted to the patients and their caregivers who have facilitated the study of these neurodegenerative diseases. V.M.Y.L. is the John H. Ware III Professor of Alzheimer's disease research. J.Q.T. is the William Maul Measey–Truman G. Schnabel, Jr. Professor of Geriatric Medicine and Gerontology. M.S.F. is supported by a Mentored Clinical Scientist Development Award from the National Institute on Aging, K08 AG20073-01. The authors acknowledge support for their research from the US National Institutes of Health (P01 AG09215, P30 AG10124, P01 AG11542, P01 AG14382, P01 AG14449, P01 AG17586, P01 NS044233). Because of space limitations in this historical perspective, many of the citations here are reviews wherein the references to the primary literature may be found.

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  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 36th and Spruce Streets, Maloney Building, 3rd Floor, Philadelphia, 19104-4283, Pennsylvania, USA

    Mark S Forman, John Q Trojanowski & Virginia M-Y Lee

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Forman, M., Trojanowski, J. & Lee, VY. Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med 10, 1055–1063 (2004). https://doi.org/10.1038/nm1113

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