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Human Molecular Genetics Advance Access published online on December 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi458
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received October 28, 2005
Revised December 2, 2005
Accepted December 14, 2005

Article

Rapamycin alleviates toxicity of different aggregate-prone proteins

Zdenek Berger 1, Brinda Ravikumar 2, Fiona M. Menzies 2, Lourdes Garcia Oroz 2, Benjamin R. Underwood 3, Menelas N. Pangalos 4, Ina Schmitt 5, Ullrich Wullner 5, Bernd O. Evert 5, Cahir J. O'Kane 6, and David C. Rubinsztein 2 *

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

* To whom correspondence should be addressed.
David C. Rubinsztein, E-mail: dcr1000{at}cam.ac.uk


  Abstract

Many neurodegenerative diseases are caused by intracellular, aggregate-prone proteins, including polyglutamine-expanded huntingtin in Huntington's disease 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 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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