title: Serine 421 regulates mutant huntingtin toxicity and clearance in mice.
abstract: 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.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Kratter
authors.forename: Hengameh
authors.initials: H
authors.lastname: Zahed
authors.forename: Alice
authors.initials: A
authors.lastname: Lau
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Tsvetkov
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Daub
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Weiberth
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Gu
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saudou
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
authors.forename: Alex
authors.initials: A
authors.lastname: Osmand
authors.forename: Joan S
authors.initials: JS
authors.lastname: Steffan
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
mesh_terms: D000409:Alanine / Q000737:chemistry; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D001522:Behavior, Animal; D022202:Chromosomes, Artificial, Bacterial; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005684:Gait; D005838:Genotype; D006801:Humans; D000071058:Huntingtin Protein / Q000737:chemistry / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012694:Serine / Q000737:chemistry*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D001224:Aspartic Acid; D012694:Serine; D046988:Proteasome Endopeptidase Complex; D000409:Alanine