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Neuron. 2015 Jan 21;85(2):303-15. doi: 10.1016/j.neuron.2014.12.019. Epub 2014 Dec 31.

Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes.

Author information

1
Medical Scientist Training Program, Roy J and Lucille A Carver College of Medicine, Iowa City, IA 52242, USA.
2
The Center for Cell and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
3
Departments of Psychiatry and Human Behavior, and Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
4
The Center for Cell and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Department of Pathology & Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: davidsonbl@email.chop.edu.

Abstract

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.

PMID:
25556834
PMCID:
PMC4355620
DOI:
10.1016/j.neuron.2014.12.019
[Indexed for MEDLINE]
Free PMC Article

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