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Potential function for the Huntingtin protein as a scaffold for selective autophagy

2014; National Academy of Sciences; Volume: 111; Issue: 47 Linguagem: Inglês

10.1073/pnas.1420103111

1091-6490

Joseph Ochaba, Tamás Lukácsovich, George Csikós, Shuqiu Zheng, Julia Margulis, Lisa Salazar, Kai Mao, Alice Lau, Sylvia Y. Yeung, Sandrine Humbert, Frédéric Saudou, Daniel J. Klionsky, Steven Finkbeiner, Scott Zeitlin, J. Lawrence Marsh, David E. Housman, Leslie M. Thompson, Joan S. Steffan,

Endoplasmic Reticulum Stress and Disease

Significance The normal function of the Huntingtin (HTT) protein is emerging. Here we report that selective autophagy requires an intact HTT protein in Drosophila and mouse CNS. We describe similarities in structure and binding activity between the C-terminal domain of HTT and the yeast autophagy scaffold protein Atg11, suggesting that HTT may normally function as a scaffold for various types of selective autophagy. Mice expressing an expanded repeat form of HTT also show deficits in protein clearance. Because autophagy is critical for clearance of cellular proteins, including mutant HTT, the impairment of normal HTT function by the polyQ expansion could suppress activity of the autophagy machinery. These results may have important implications when evaluating therapeutic strategies for HD.