Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease

Brinda Ravikumar, Coralie Vacher, Zdenek Berger, Janet E. Davies, Shouqing Luo, Lourdes G. Oroz, Francesco Scaravilli, Douglas F. Easton, Rainer Duden, Cahir J. O'Kane, David C. Rubinsztein*

*Korrespondierende/r Autor/-in für diese Arbeit
1789 Zitate (Scopus)

Abstract

Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.

OriginalspracheEnglisch
ZeitschriftNature Genetics
Jahrgang36
Ausgabenummer6
Seiten (von - bis)585-595
Seitenumfang11
ISSN1061-4036
DOIs
PublikationsstatusVeröffentlicht - 06.2004

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

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