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.

Author affiliations

1. Christopher A. Ross and Michelle A. Poirier are in the Division of Neurobiology, Department of Psychiatry at Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.
   Email: caross@jhu.edu
   Email: mpoirie1@jhmi.edu

Published online 15 September 2005

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