Rapamycin-induced autophagy cleared toxic clumped proteins and improved symptoms in fly and mouse models of Huntington's disease.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Drosophila and mouse models of Huntington's disease |
| Journal | Nature Genetics |
| Year | 2004 |
| Peer reviewed | Yes |
| Source | DOI 10.1038/ng1362 · PMID 15146184 |
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.
| Intervention | Rapamycin (mTOR inhibition) |
| Target | mTOR / autophagy |
| Model | Drosophila and mouse Huntington's disease models |
| Effect | mTOR inhibition induces autophagy and reduces polyglutamine toxicity in Huntington's disease models |