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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrophy
  • Disease Models, Animal
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Lipogenesis / genetics
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Monomeric GTP-Binding Proteins / metabolism*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Neostriatum / metabolism*
  • Neostriatum / pathology
  • Neuropeptides / metabolism*
  • Phenotype
  • Ras Homolog Enriched in Brain Protein
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Multiprotein Complexes
  • Neuropeptides
  • Ras Homolog Enriched in Brain Protein
  • Rheb protein, mouse
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • GTP-Binding Proteins
  • Rasd2 protein, mouse
  • Monomeric GTP-Binding Proteins