title: N-terminal Huntingtin Knock-In Mice: Implications of Removing the N-terminal Region of Huntingtin for Therapy.
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.
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.|Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.|Graduate School of the Chinese Academy of Sciences, Beijing, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Chuan-En
authors.initials: CE
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.|Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.|Graduate School of the Chinese Academy of Sciences, Beijing, China.
authors.forename: Guohao
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Gaertig
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
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, China.|Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051379:Mice; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D010641:Phenotype
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine