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Induction of autophagy with catalytic mTOR inhibitors reduces huntingtin aggregates in a neuronal cell model.

Abstract：

:Huntington's disease is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. This expansion produces a mutant form of the huntingtin protein, which contains an elongated polyglutamine stretch at its amino-terminus. Mutant huntingtin may adopt an aberrant, aggregation-prone conformation predicted to start the pathogenic process leading to neuronal dysfunction and cell death. Thus, strategies reducing mutant huntingtin may lead to disease-modifying therapies. We investigated the mechanisms and molecular targets regulating huntingtin degradation in a neuronal cell model. We first found that mutant and wild-type huntingtin displayed strikingly diverse turn-over kinetics and sensitivity to proteasome inhibition. Then, we show that autophagy induction led to accelerate degradation of mutant huntingtin aggregates. In our neuronal cell model, allosteric inhibition of mTORC1 by everolimus, a rapamycin analogue, did not induce autophagy or affect aggregate degradation. In contrast, this occurred in the presence of catalytic inhibitors of both mTOR complexes mTORC1 and mTORC2. Our data demonstrate the existence of an mTOR-dependent but everolimus-independent mechanism regulating autophagy and huntingtin-aggregate degradation in cells of neuronal origin.

journal_name

J Neurochem

journal_title

Journal of neurochemistry

authors

Roscic A,Baldo B,Crochemore C,Marcellin D,Paganetti P

doi

10.1111/j.1471-4159.2011.07435.x

subject

Has Abstract

pub_date

2011-10-01 00:00:00

pages

398-407

issue

2

eissn

0022-3042

issn

1471-4159

journal_volume

119

pub_type

杂志文章

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