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.

Recycle or die: The role of autophagy in cardioprotection

“…Many studies have found that inhibition of the UPS causes upregulation of autophagy, and that suppression of autophagy leads to accumulation of polyubiqutinated protein aggregates [60][61][62][63][64]. Also, rapamycin treatment to activate autophagy increased clearance of aggregate-prone proteins and reduced the appearance of protein aggregates in vitro and in vivo [39,65,66]. In the heart, cardiac specific deletion of Atg5 resulted in increased polyubiquitinated protein levels and proteasome activity [30].…”

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…167 Autophagy has been described for intracellular protein aggregates such as polyQ-huntingtin and ␣-synuclein aggregates, and also for tau. 168,169 Rapamycin inhibits mTOR (mammalian target of rapamycin), thereby promoting autophagy. In a Drosophila fruit fly model expressing wild-type or R406W mutant tau, treatment with rapamycin induced autophagic tau degradation and diminished tau-induced toxicity.…”

“…In a Drosophila fruit fly model expressing wild-type or R406W mutant tau, treatment with rapamycin induced autophagic tau degradation and diminished tau-induced toxicity. 169 It has been speculated that the nonclassic, proteasome-independent K63 ubiquitin pathway is involved in the autophagic route of tau. This notion is supported by the finding that P301L tau-positive inclusions in a neuronal cell line were cleared after stimulation of autophagy, a mechanism that was impaired by coexpression of the ubiquitin mutant K63R.…”

Eating on the fly: Function and regulation of autophagy during cell growth, survival and death in Drosophila

“…Treatment of fly and mouse models of neurodegenerative diseases, including mutant tau and the expanded polyglutamine proteins that cause Huntington's disease and spinobulbar muscular atrophy (SBMA), with the inducer of autophagy rapamycin (an inhibitor of mTOR) reduces aggregate prone proteins and suppresses degenerative phenotypes. [24][25][26] Significantly, this suppression of neurodegenerative phenotypes by rapamycin treatment depends on Atg gene function. 25,26 It is not completely clear if the increased accumulation of autophagosomes in these disease models is caused by either increased levels of autophagy, decreased clearance of autophagosomes by lysosomes, or both increased autophagy and decreased clearance, and this remains an important issue to resolve.…”