title: Rapamycin alleviates toxicity of different aggregate-prone proteins.
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.
authors.affiliation: Department of Medical Genetics,Cambridge Institute for Medical Research,Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Berger
authors.forename: Brinda
authors.initials: B
authors.lastname: Ravikumar
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Menzies
authors.forename: Lourdes Garcia
authors.initials: LG
authors.lastname: Oroz
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Underwood
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Ina
authors.initials: I
authors.lastname: Schmitt
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wullner
authors.forename: Bernd O
authors.initials: BO
authors.lastname: Evert
authors.forename: Cahir J
authors.initials: CJ
authors.lastname: O'Kane
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D020123:Sirolimus / Q000494:pharmacology*; D019680:Trinucleotide Repeat Expansion; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity
chemical_list: D010455:Peptides; D011506:Proteins; D016875:tau Proteins; C019529:polyalanine; C097188:polyglutamine; D020123:Sirolimus