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Human Molecular Genetics Advance Access originally published online on December 20, 2005
Human Molecular Genetics 2006 15(3):433-442; doi:10.1093/hmg/ddi458
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© The Author 2005. Published by Oxford University Press. All rights reserved.
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Rapamycin alleviates toxicity of different aggregate-prone proteins

Zdenek Berger1,2, Brinda Ravikumar1, Fiona M. Menzies1, Lourdes Garcia Oroz1, Benjamin R. Underwood1,3, Menelas N. Pangalos5, Ina Schmitt4, Ullrich Wullner4, Bernd O. Evert4, Cahir J. O'Kane2 and David C. Rubinsztein1,*

1Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK, 2Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK, 3Suffolk Mental Health Partnership NHS Trust, Department of Psychiatry, Wedgwood house, West Suffolk Hospital, Bury St Edmunds IP33 2QZ, UK, 4Universitätsklinikum Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany and 5Wyeth Research, CN 8000, Princeton, NJ 08543, USA

* To whom correspondence should be addressed. Email: dcr1000{at}cam.ac.uk

Received October 28, 2005; Revised December 2, 2005; Accepted December 14, 2005

Many neurodegenerative diseases are caused by intracellular, aggregate-prone proteins, including polyglutamine-expanded huntingtin in Huntington's disease (HD) and mutant tau in fronto-temporal dementia/tauopathy. Previously, we showed that rapamycin, an autophagy inducer, enhances mutant huntingtin fragment clearance and attenuated toxicity. Here we show much wider applications for this approach. Rapamycin enhances the autophagic clearance of different proteins with long polyglutamines and a polyalanine-expanded protein, and reduces their toxicity. Rapamycin also reduces toxicity in Drosophila expressing wild-type or mutant forms of tau and these effects can be accounted for by reductions in insoluble tau. Thus, our studies suggest that the scope for rapamycin as a potential therapeutic in aggregate diseases may be much broader than HD or even polyglutamine diseases.


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