Rapamycin alleviates toxicity of different aggregate-prone proteins.
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.
Berger
Zdenek
Z
Department of Medical Genetics,Cambridge Institute for Medical Research,Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
Ravikumar
Brinda
B
Menzies
Fiona M
FM
Oroz
Lourdes Garcia
LG
Underwood
Benjamin R
BR
Pangalos
Menelas N
MN
Schmitt
Ina
I
Wullner
Ullrich
U
Evert
Bernd O
BO
O'Kane
Cahir J
CJ
Rubinsztein
David C
DC
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
D010455:Peptides; D011506:Proteins; D016875:tau Proteins; C019529:polyalanine; C097188:polyglutamine; D020123:Sirolimus