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Serine 421 regulates mutant huntingtin toxicity and clearance in mice
Serine 421 regulates mutant huntingtin toxicity and clearance in mice JOURNAL OF CLINICAL INVESTIGATION Kratter, I. H., Zahed, H., Lau, A., Tsvetkov, A. S., Daub, A. C., Weiberth, K. F., Gu, X., Saudou, F., Humbert, S., Yang, X., Osmand, A., Steffan, J. S., Masliah, E., Finkbeiner, S. 2016; 126 (9): 3585–97Abstract
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.
View details for DOI 10.1172/JCI80339
View details for Web of Science ID 000382513400036
View details for PubMedID 27525439
View details for PubMedCentralID PMC5004962