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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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.
The authors declare no competing financial interests.
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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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