Research ArticleNeurodegeneration

Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease

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Science Signaling  28 Oct 2014:
Vol. 7, Issue 349, pp. ra103
DOI: 10.1126/scisignal.2005633

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Hunting the Pathways in Huntington’s Disease

Huntington’s disease (HD) is caused by a mutant form of the protein huntingtin (Htt), which causes neurodegeneration in the striatum. HD-associated symptoms are alleviated by inhibition of the kinase mTOR, which is a key regulator of protein synthesis and is normally activated by amino acids. In primary mouse striatal neuronal cells, Pryor et al. found that wild-type Htt enhanced mTOR signaling in response to amino acids, and mutant Htt further potentiated mTOR activity. Mutant Htt bound more effectively than wild-type Htt to the guanosine triphosphatase (GTPase) Rheb and facilitated the activating interaction between Rheb and mTOR. Striatum-specific deletion of the gene encoding TSC1, an inhibitor of mTOR, accelerated the onset of HD phenotypes in mice, consistent with excessive mTOR activity contributing to HD. The findings identify a pathway by which mutant Htt contributes to HD pathology.

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