TY - JOUR AU - Kratter, Ian H. AU - Zahed, Hengameh AU - Lau, Alice AU - Tsvetkov, Andrey S. AU - Daub, Aaron C. AU - Weiberth, Kurt F. AU - Gu, Xiaofeng AU - Saudou, Frédéric AU - Humbert, Sandrine AU - Yang, X. William AU - Osmand, Alex AU - Steffan, Joan S. AU - Masliah, Eliezer AU - Finkbeiner, Steven T1 - Serine 421 regulates mutant huntingtin toxicity and clearance in mice PY - 2016/09/01/ AB - Huntington’s disease (HD) is a progressive, adult-onset neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the N-terminal region of the protein huntingtin (HTT). There are no cures or disease-modifying therapies for HD. HTT has a highly conserved Akt phosphorylation site at serine 421, and prior work in HD models found that phosphorylation at S421 (S421-P) diminishes the toxicity of mutant HTT (mHTT) fragments in neuronal cultures. However, whether S421-P affects the toxicity of mHTT in vivo remains unknown. In this work, we used murine models to investigate the role of S421-P in HTT-induced neurodegeneration. Specifically, we mutated the human mHTT gene within a BAC to express either an aspartic acid or an alanine at position 421, mimicking tonic phosphorylation (mHTT-S421D mice) or preventing phosphorylation (mHTT-S421A mice), respectively. Mimicking HTT phosphorylation strongly ameliorated mHTT-induced behavioral dysfunction and striatal neurodegeneration, whereas neuronal dysfunction persisted when S421 phosphorylation was blocked. We found that S421 phosphorylation mitigates neurodegeneration by increasing proteasome-dependent turnover of mHTT and reducing the presence of a toxic mHTT conformer. These data indicate that S421 is a potent modifier of mHTT toxicity and offer in vivo validation for S421 as a therapeutic target in HD. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI80339 VL - 126 IS - 9 UR - https://doi.org/10.1172/JCI80339 SP - 3585 EP - 3597 PB - The American Society for Clinical Investigation ER -