[ARTICLE]

Berger, Zdenek^1,2; Ravikumar, Brinda¹; Menzies, Fiona M.¹; Oroz, Lourdes Garcia¹; Underwood, Benjamin R.^1,3; Pangalos, Menelas N.⁵; Schmitt, Ina⁴; Wullner, Ullrich⁴; Evert, Bernd O.⁴; O'Kane, Cahir J.²; Rubinsztein, David C.^1,*

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

⁵Wyeth Research, CN 8000, Princeton, NJ 08543, USA

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

^*To whom correspondence should be addressed. Email: dcr1000@cam.ac.uk

Abstract

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.