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Huntingtin enhances Huntington's disease via activating mTORC1 signaling pathway

 

Huntington's disease (HD), also called Hunington's chorea, usually causes muscle discoordination and cognitive decline. This disease is a neurodegenerative genetic disorder that associated with an expansion of ITI5 gene, leading to long N-terminal polyglutamine (poly-Q) tracts in huntingtin (Htt). William Pryor et al., from The Scripps Research Institute, found Htt enhances signaling of mechanistic target of rapamycin complex 1 (mTORC1). The article was published on Science Signaling, recently.

 

Researchers found knocking out or overexpressing Htt led to attenuate or increase activity of mTORC1 in certain types of cells, respectively. In addition, compared to wild-type Htt, poly-Q-expanded Htt had a greater effect on promoting mTORC1 signaling in striatal cells. By further investigating the mechanism of Htt increasing mTOR activity, researchers found that Htt interacted with GTP-binding protein Rheb, a protein that stimulates mTOR activity. Two proteins formed a temary complex with mTOR, then. Moreover, striatum-specific knocking out the gene, which encodes a negative regulator of mTORC1, aggravated phenotypes and caused death in an HD mouse model.

 

The study provides a novel perspective on mTORC1 pathway by looking into the relationship between Htt and mTOR. Poly-Q-expanded Htt and mTORC1 signaling may play crucial roles in the development of HD, and may have therapeutic importance in the future.

 

Reference:
Sci Signal. 2014 Oct 28;7(349):ra103.

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