Review Article | Published:

The roles of intracellular protein-degradation pathways in neurodegeneration

Nature volume 443, pages 780786 (19 October 2006) | Download Citation

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Abstract

Many late-onset neurodegenerative diseases, including Parkinson's disease and Huntington's disease, are associated with the formation of intracellular aggregates by toxic proteins. It is therefore crucial to understand the factors that regulate the steady-state levels of these 'toxins', at both the synthetic and degradation stages. The degradation pathways acting on such aggregate-prone cytosolic proteins include the ubiquitin–proteasome system and macroautophagy. Dysfunction of the ubiquitin–proteasome or macroautophagy pathways might contribute to the pathology of various neurodegenerative conditions. However, enhancing macroautophagy with drugs such as rapamycin could offer a tractable therapeutic strategy for a number of these diseases.

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Acknowledgements

I am grateful to B. Ravikumar and M. Futter for critical comments on the manuscript and L. Smith for help with manuscript preparation. The work in my laboratory covered by this review has been funded by a Wellcome Trust Senior Fellowship in Clinical Science, a Medical Research Council (MRC) Programme Grant, Wyeth, and European Union Framework VI (EUROSCA).

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Affiliations

  1. Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK. dcr1000@hermes.cam.ac.uk

    • David C. Rubinsztein

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Competing interests

D.C.R. is an inventor on patents relating to the use of autophagy induction for treating neurodegenerative diseases. His laboratory has received grant funding from Wyeth, which makes rapamycins.

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https://doi.org/10.1038/nature05291

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