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What is the role of protein aggregation in neurodegeneration?

Nature Reviews Molecular Cell Biology volume 6, pages 891–898 (2005)Cite this article

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.

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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.

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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.

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  1. the Division of Neurobiology, Department of Psychiatry at Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Christopher A. Ross & Michelle A. Poirier

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DATABASES

OMIM

AD

ALS

familial British dementia

familial Danish dementia

frontotemporal dementia

HD

PD

progressive supranuclear palsy

Swiss-Prot

α-synuclein

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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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