Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis

• Type of Material: Article
• Authors: Guohai Wang, University of Chinese Academy of Sciences; Xudong Liu, University of Chinese Academy of Sciences; Shihua Li, Emory University; Marta A. Gaertig, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2016-03-22
• Publisher: United States National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2016 National Academy of Sciences.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1524575113
• Title of Journal or Parent Work: PNAS
• Volume: 113
• Issue: 12
• Start Page: 3359
• End Page: 3364
• Grant/Funding Information: This work was supported by National Natural Science Foundation of China Grant 91332206, National Institutes of Health Grants NS041669 and AG019206 (to X.-J.L.) and NS095279 (to S.L.), and the State Key Laboratory of Molecular Developmental Biology, China.
• Keywords: degeneration; Animals; Huntingtin Protein; Nerve Tissue Proteins; Mice, Knockout; Acute Disease; Neurons; Nuclear Proteins; aging; Huntingtin; acinus; pancreas; Mice; Pancreatitis
• Research Categories: Biology, Genetics; Health Sciences, Human Development; Biology, Molecular

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.