title: Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis.
abstract: The Huntington's disease (HD) protein, huntingtin (HTT), is essential for early development. Because suppressing the expression of mutant HTT is an important approach to treat the disease, we must first understand the normal function of Htt in adults versus younger animals. Using inducible Htt knockout mice, we found that Htt depletion does not lead to adult neurodegeneration or animal death at >4 mo of age, which was also verified by selectively depleting Htt in neurons. On the other hand, young Htt KO mice die at 2 mo of age of acute pancreatitis due to the degeneration of pancreatic acinar cells. Importantly, Htt interacts with the trypsin inhibitor, serine protease inhibitor Kazal-type 3 (Spink3), to inhibit activation of digestive enzymes in acinar cells in young mice, and transgenic HTT can rescue the early death of Htt KO mice. These findings point out age- and cell type-dependent vital functions of Htt and the safety of knocking down neuronal Htt expression in adult brains as a treatment.
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Guohao
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Marta A
authors.initials: MA
authors.lastname: Gaertig
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; xli2@emory.edu sli@emory.edu.
authors.forename: Shihua
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; xli2@emory.edu sli@emory.edu.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
mesh_terms: D000208:Acute Disease; D000818:Animals; D000071058:Huntingtin Protein; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D010195:Pancreatitis / Q000235:genetics*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins
keywords: Huntingtin; acinus; aging; degeneration; pancreas