Science Signaling Podcast: 28 October 2014

• Published in: Science signaling 2014-10, Vol.7 (349)
• Main Authors: Pryor, William M., Subramaniam, Srinivasa, VanHook, Annalisa M.
• Format: Article
• Language: English
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.aaa0852

A mutant form of huntingtin associated with early-onset Huntington's disease promotes anabolic signaling that contributes to motor abnormalities and death in mice. This Podcast features an interview with William Pryor and Srinivasa Subramaniam, authors of a Research Article that appears in the 28 October 2014 issue of Science Signaling , about how the huntingtin protein (Htt) stimulates signaling that contributes to Huntington's disease–like symptoms in mice. Htt is ubiquitously expressed and contains an amino-terminal polyglutamine tract. Whereas normal forms of Htt contain up to 35 glutamine residues in this region, forms of Htt in Huntington's disease patients contain more than 36 glutamine residues. Expansion of the polyglutamine tract is sufficient to cause disease, because increasing the number of glutamines in this region in mice causes motor defects and other pathologies typical of Huntington's disease. Although it is clear that expansion of the polyglutamine tract of Htt contributes to Huntington's disease, it is not clear how normal forms of Htt function in cell biology or how polyglutamine-expanded forms of Htt cause disease. Pryor et al . report that Htt promotes anabolic signaling through the mechanistic target of rapamycin complex 1 (mTORC1) and that polyglutamine-expanded forms of Htt enhance mTORC1 signaling. Increasing mTORC1 signaling in a mouse model of Huntington's disease led to earlier onset of disease symptoms.