title: A novel nuclear DnaJ protein, DNAJC8, can suppress the formation of spinocerebellar ataxia 3 polyglutamine aggregation in a J-domain independent manner.
abstract: Polyglutamine (polyQ) diseases comprise neurodegenerative disorders caused by expression of expanded polyQ-containing proteins. The cytotoxicity of the expanded polyQ-containing proteins is closely associated with aggregate formation. In this study, we report that a novel J-protein, DNAJ (HSP40) Homolog, Subfamily C, Member 8 (DNAJC8), suppresses the aggregation of polyQ-containing protein in a cellular model of spinocerebellar ataxia type 3 (SCA3), which is also known as Machado-Joseph disease. Overexpression of DNAJC8 in SH-SY5Y neuroblastoma cells significantly reduced the polyQ aggregation and apoptosis, and DNAJC8 was co-localized with the polyQ aggregation in the cell nucleus. Deletion mutants of DNAJC8 revealed that the C-terminal domain of DNAJC8 was essential for the suppression of polyQ aggregation, whereas the J-domain was dispensable. Furthermore, 22-mer oligopeptide derived from C-termilal domain could suppress the polyQ aggregation. These results indicate that DNAJC8 can suppress the polyQ aggregation via a distinct mechanism independent of HSP70-based chaperone machinery and have a unique protective role against the aggregation of expanded polyQ-containing proteins such as pathogenic ataxin-3 proteins.
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan; Department of Neurology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Ito
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kamiguchi
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nakanishi
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Alice
authors.initials: A
authors.lastname: Sokolovskya
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirohashi
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Murai
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kanaseki
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tsukahara
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Kochin
authors.affiliation: Department of Neurology, Clinical Brain Research Laboratory, Toyokura Memorial Hall, Sapporo Yamano-ue Hospital, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Department of Neurology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan. Electronic address: torigoe@sapmed.ac.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
mesh_terms: D000067699:Ataxin-3 / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D017827:Machado-Joseph Disease / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C494653:DNAJC8 protein, human; D050956:HSP40 Heat-Shock Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: Ataxin-3; DNAJC8; PolyQ disease; Spinocerebellar ataxia type 3