Neuron
Volume 85, Issue 2, 21 January 2015, Pages 303-315
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Article
Reinstating Aberrant mTORC1 Activity in Huntington’s Disease Mice Improves Disease Phenotypes

https://doi.org/10.1016/j.neuron.2014.12.019Get rights and content
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Highlights

  • Impaired striatal mTORC1 activity is upstream of HD phenotypes

  • mTORC1activation reverses HD phenotypes

  • mTORC1activation improves striatal cell function in HD mouse brains

  • Restoring Rhes improves HD associated motor phenotypes

Summary

Huntington’s disease (HD) is caused by a polyglutamine tract expansion in huntingtin (HTT). Despite HTTs ubiquitous expression, there is early and robust vulnerability in striatum, the cause of which is poorly understood. Here, we provide evidence that impaired striatal mTORC1 activity underlies varied metabolic and degenerative phenotypes in HD brain and show that introducing the constitutively active form of the mTORC1 regulator, Rheb, into HD mouse brain, alleviates mitochondrial dysfunction, aberrant cholesterol homeostasis, striatal atrophy, impaired dopamine signaling, and increases autophagy. We also find that the expression of Rhes, a striatum-enriched mTOR activator, is reduced in HD patient and mouse brain and that exogenous addition of Rhes alleviates motor deficits and improves brain pathology in HD mice. Our combined work indicates that impaired Rhes/mTORC1 activity in HD brain may underlie the notable striatal susceptibility and thus presents a promising therapeutic target for HD therapy.

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