title: p62 Deficiency Enhances α-Synuclein Pathology in Mice.
abstract: In Lewy body disease (LBD) such as dementia with LBs and Parkinson's disease, several lines of evidence show that disrupted proteolysis occurs. p62/SQSTM1 (p62) is highly involved with intracellular proteolysis and is a component of ubiquitin-positive inclusions in various neurodegenerative disorders. However, it is not clear whether p62 deficiency affects inclusion formation and abnormal protein accumulation. To answer this question, we used a mouse model of LBD that lacks p62, and found that LB-like inclusions were observed in transgenic mice that overexpressed α-synuclein (Tg mice) with or without the p62 protein. p62 deficiency enhanced α-synuclein pathology with regard to the number of inclusions and staining intensity compared with Tg mice that expressed p62. To further investigate the molecular mechanisms associated with the loss of p62 in Tg mice, we assessed the mRNA and protein levels of several molecules, and found that the neighbor of the brca1 gene (NBr1), which is functionally and structurally similar to p62, is increased in Tg mice without p62 compared with control Tg mice. These findings suggest that p62 and NBR1 affect the pathogenesis of neurodegenerative diseases through the cooperative modulation of α-synuclein aggregation.
authors.affiliation: Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Tanji
authors.affiliation: Department of Neuroanatomy, Cell Biology and Histology, University of Tsukuba, Tsukuba, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Odagiri
authors.affiliation: Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miki
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maruyama
authors.affiliation: Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nikaido
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Junsei
authors.initials: J
authors.lastname: Mimura
authors.affiliation: Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Mori
authors.affiliation: Majors of Medical Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Warabi
authors.affiliation: Majors of Medical Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yanagawa
authors.affiliation: Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueno
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Wakabayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D006360:Heat-Shock Proteins / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D011506:Proteins / Q000378:metabolism; D059748:Proteolysis; D000071456:Sequestosome-1 Protein; D013312:Stress, Physiological; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; C486326:Nbr1 protein, mouse; D011506:Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D051844:alpha-Synuclein
keywords: Lewy body disease; Parkinson's disease; p62/Sequestsome 1/SQSTM1; proteolysis; stress; α-synuclein