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

• DOI: 10.1126/scisignal.2005633
• Publication Date: 2014-10-28T18:43:57Z
• Authors: William M. Pryor; Marta Biagioli; Neelam Shahani; Supriya Swarnkar; Wen-Chin Huang; Damon T. Page; Marcy E. MacDonald; Srinivasa Subrama...
• Keywords: RHEB; TSC1; Small GTPase

In patients with Huntington's disease (HD), the protein huntingtin (Htt) has an expanded polyglutamine (poly-Q) tract. HD results in early loss of medium spiny neurons striatum, which impairs motor and cognitive functions. Identifying physiological role molecular functions Htt may yield insight into pathogenesis. We found that promotes signaling by mTORC1 [mechanistic target rapamycin (mTOR) complex 1] this is potentiated poly-Q-expanded Htt. Knocking out mouse embryonic stem cells or human kidney attenuated amino acid-induced activity, whereas overexpressing wild-type striatal neuronal increased basal mTOR activity. Striatal expressing endogenous showed increase number size puncta on perinuclear regions compared to Pull-down experiments indicated acids stimulated interaction guanosine triphosphatase (GTPase) Rheb (a stimulates activity), forms a ternary mTOR. Pharmacologically inhibiting PI3K (phosphatidylinositol 3-kinase) knocking down abrogated activity induced expression amino-terminal fragment. Moreover, striatum-specific deletion TSC1, encoding tuberous sclerosis 1, negative regulator mTORC1, accelerated onset coordination abnormalities caused premature death model. Together, our findings demonstrate mutant contributes pathogenesis enhancing