N-terminal Huntingtin Knock-In Mice: Implications of Removing the N-terminal Region of Huntingtin for Therapy

• Type of Material: Article
• Authors: Xudong Liu, Chinese Academy of Sciences; Chuanen Wang, Emory University; Yan Hong, Emory University; Ting Zhao, Emory University; Guohao Wang, Emory University; Marta A. Gaertig, Emory University; Miao Sun, Emory University; Shihua Li, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2016-05-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Liu et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pgen.1006083
• Title of Journal or Parent Work: PLoS Genetics
• ISSN: 1553-7390
• Volume: 12
• Issue: 5
• Start Page: e1006083
• End Page: e1006083
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (NS041449, AG019206) XJL, (NS095279) SL, and the National Key Basic Research Program of China (2012CBA01304), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13000000), and the State Key Laboratory of Molecular Developmental Biology, China.
• Keywords: Neurites; Neurons; Mouse models; Neostriatum; Phenotypes; Astrocytes; Huntington disease; Embryos
• Research Categories: Health Sciences, General; Biology, Genetics; Biology, Neuroscience

Abstract

The Huntington’s disease (HD) protein, huntingtin (HTT), is a large protein consisting of 3144 amino acids and has conserved N-terminal sequences that are followed by a polyglutamine (polyQ) repeat. Loss of Htt is known to cause embryonic lethality in mice, whereas polyQ expansion leads to adult neuronal degeneration. Whether N-terminal HTT is essential for neuronal development or contributes only to late-onset neurodegeneration remains unknown. We established HTT knock-in mice (N160Q-KI) expressing the first 208 amino acids of HTT with 160Q, and they show age-dependent HTT aggregates in the brain and neurological phenotypes. Importantly, the N-terminal mutant HTT also preferentially accumulates in the striatum, the brain region most affected in HD, indicating the importance of N-terminal HTT in selective neuropathology. That said, homozygous N160Q-KI mice are also embryonic lethal, suggesting that N-terminal HTT alone is unable to support embryonic development. Using Htt knockout neurons, we found that loss of Htt selectively affects the survival of developing neuronal cells, but not astrocytes, in culture. This neuronal degeneration could be rescued by a truncated HTT lacking the first 237 amino acids, but not by N-terminal HTT (1–208 amino acids). Also, the rescue effect depends on the region in HTT known to be involved in intracellular trafficking. Thus, the N-terminal HTT region may not be essential for the survival of developing neurons, but when carrying a large polyQ repeat, can cause selective neuropathology. These findings imply a possible therapeutic benefit of removing the N-terminal region of HTT containing the polyQ repeat to treat the neurodegeneration in HD.