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

  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},
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
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
In vivo genetic evidence is provided that autophagy genes suppress the accumulation of polyQ aggregates and protect cells from disease caused by polyQ toxicity, and results in enhanced neurodegeneration.
Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease
Rilmenidine administration attenuated the signs of disease in a HD mouse model and reduced levels of the mutant huntingtin fragment, and the data suggests that it should be considered for the treatment of HD and related conditions.
Small molecules enhance autophagy and reduce toxicity in Huntington's disease models.
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
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
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.
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
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.


Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy.
Exon 1 of the HD gene with expanded polyglutamine [poly(Q)] repeats and enhanced green fluorescent protein tagged to 19 alanines is used as models for aggregate-prone proteins, to investigate the pathways mediating their degradation and re-examined the role of the proteasome.
Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila
It is shown that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF).
Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease
Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity.
Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease
  • E. Hockly, V. Richon, G. Bates
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2003
Preclinical trials with suberoylanilide hydroxamic acid (SAHA), a potent HDAC inhibitor, show that SAHA crosses the blood–brain barrier and increases histone acetylation in the brain, clearly validating the pursuit of this class of compounds as HD therapeutics.
Formation of polyglutamine inclusions in non-CNS tissue.
The formation of inclusions in non-CNS tissues will be particularly useful with respect to in vivo monitoring of pharmaceutical agents selected for their ability to prevent polyglutamine aggregation in vitro, without the requirement that the agent can cross the blood-brain barrier in the first instance.
Huntingtin Expression Stimulates Endosomal–Lysosomal Activity, Endosome Tubulation, and Autophagy
The huntingtin-enriched cytoplasmic vacuoles formed in vitro internalized the lysosomal enzyme cathepsin D in proportion to the polyglutamine-length in huntingtin, which contributes to huntingtin proteolysis and to an autophagic process of cell death.
Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease.
Stable inducible neuronal (PC12) cell lines that express huntingtin exon 1 with varying CAG repeat lengths under doxycycline (dox) control suggest novel targets for the HD mutation and were compatible with impaired cAMP response element (CRE)-mediated transcription, which was confirmed using CRE-luciferase reporter assays.
Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin.
Transgenic mice that express a cDNA encoding an N-terminal fragment of huntingtin with 82, 44 or 18 glutamines develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely, consistent with the idea that N-Terminal fragments of Huntington's disease with a repeat expansion are toxic to neurons, and that N.terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.