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

@article{Ravikumar2004InhibitionOM,
  title={Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease},
  author={Brinda Ravikumar and Coralie Vacher and Zdeněk Berger and Janet E. Davies and Shouqing Luo and Lourdes Garc{\'i}a Oroz and Francesco Scaravilli and Douglas F. Easton and Rainer Duden and Cahir J. O'Kane and David C. Rubinsztein},
  journal={Nature Genetics},
  year={2004},
  volume={36},
  pages={585-595}
}
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… 
Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies
TLDR
Various drugs and pathways inducing autophagy, which may be potential therapeutic approaches for Huntington's disease and related conditions are described.
Autophagy Genes Protect Against Disease Caused by Polyglutamine Expansion Proteins in Caenorhabditis elegans
TLDR
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Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease
TLDR
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Small molecules enhance autophagy and reduce toxicity in Huntington's disease models.
TLDR
Proof of principle is demonstrated for a new approach for discovery of small-molecule modulators of mammalian autophagy for therapeutic potential in Huntington's disease cell and Drosophila melanogaster models.
Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation
Rapamycin Inhibits Polyglutamine Aggregation Independently of Autophagy by Reducing Protein Synthesis
TLDR
It is shown that rapamycin reduces the amount of soluble polyQ protein via a modest inhibition of protein synthesis that in turn significantly reduces the formation of insoluble polyQprotein and IB formation, suggesting that rap amycin may alleviate polyQ disease pathology via its effect on global protein synthesis.
Ubiquilin-1 Overexpression Increases the Lifespan and Delays Accumulation of Huntingtin Aggregates in the R6/2 Mouse Model of Huntington's Disease
TLDR
It is demonstrated that overexpression of ubiqulin-1, which facilitates protein clearance through the proteasome and autophagy pathways, reduces huntingtin aggregates and toxicity in mammalian cell and invertebrate models of HD, and that restoration of ubiquilin levels would delay HD symptoms and pathology.
A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin.
TLDR
This work uses the mTOR inhibitor rapamycin in combination with lithium to counteract the autophagy inhibitory effects of mTOR activation resulting from lithium treatment and provides proof-of-principle for this rational combination treatment approach in vivo by showing greater protection against neurodegeneration in an HD fly model with TOR inhibition and lithium.
Neferine Attenuates the Protein Level and Toxicity of Mutant Huntingtin in PC-12 Cells via Induction of Autophagy
TLDR
Nferine, isolated from the lotus seed embryo of Nelumbo nucifera, is identified, which is able to induce autophagy through an AMPK-mTOR-dependent pathway and is crucial for its further development into a potential therapeutic agent for neurodegenerative disorders in the future.
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