title: Depletion of p62 reduces nuclear inclusions and paradoxically ameliorates disease phenotypes in Huntington's model mice.
abstract: Huntington's disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine (polyQ) tracts. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here, we investigated the effect of p62 depletion in three HD model mice: R6/2, HD190QG and HD120QG mice. We found that loss of p62 in these models led to longer life spans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyQ length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt without NLS, however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD model mice, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan, Laboratory for Structural Neuropathology, Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan, CREST (Core Research for Evolutionary Science and Technology), JST, Tokyo 102-0076, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kurosawa
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Laboratory for Structural Neuropathology, Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan, CREST (Core Research for Evolutionary Science and Technology), JST, Tokyo 102-0076, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Matsumoto
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Laboratory for Structural Neuropathology, Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan, CREST (Core Research for Evolutionary Science and Technology), JST, Tokyo 102-0076, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
authors.affiliation: Laboratory for Structural Neuropathology.
authors.forename: Misako
authors.initials: M
authors.lastname: Okuno
authors.affiliation: Laboratory for Structural Neuropathology.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Kurosawa-Yamada
authors.affiliation: Laboratory for Structural Neuropathology.
authors.forename: Chika
authors.initials: C
authors.lastname: Washizu
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Laboratory for Structural Neuropathology, Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Department of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Tottori 683-8504, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaso
authors.affiliation: Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan and.
authors.forename: Toru
authors.initials: T
authors.lastname: Yanagawa
authors.affiliation: Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan and.
authors.forename: Eiji
authors.initials: E
authors.lastname: Warabi
authors.affiliation: Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Shimogori
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Neurology.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Laboratory for Structural Neuropathology, Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan, CREST (Core Research for Evolutionary Science and Technology), JST, Tokyo 102-0076, Japan nnukina@juntendo.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001343:Autophagy; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006816:Huntington Disease / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism; D045586:Intranuclear Inclusion Bodies / Q000235:genetics*; D008136:Longevity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D059748:Proteolysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010455:Peptides; C097188:polyglutamine