title: Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases.
abstract: The sigma-1 receptor (SIGMAR1) is now known to be one of the endoplasmic reticulum (ER) chaperones, which participate in the degradation of misfolded proteins in cells via the ER-related degradation machinery linked to the ubiquitin-proteasome pathway. Mutations of the SIGMAR1 gene are implicated in the pathogenesis of familial frontotemporal lobar degeneration and motor neuron disease. Involvement of ER dysfunction in the formation of inclusion bodies in various neurodegenerative diseases has also become evident. We performed immunohistochemical staining to clarify the localization of SIGMAR1 in the brains of patients with neurodegenerative disorders, including trans-activation response DNA protein 43 (TDP-43) proteinopathy, tauopathy, α-synucleinopathy, polyglutamine disease and intranuclear inclusion body disease (INIBD). Double-immunocytofluorescence and Western blot analyses of cultured cells were also performed to investigate the role of SIGMAR1 using a specific exportin 1 inhibitor, leptomycin B and an ER stress inducer, thapsigargin. SIGMAR1 was consistently shown to be co-localized with neuronal nuclear inclusions in TDP-43 proteinopathy, five polyglutamine diseases and INIBD, as well as in intranuclear Marinesco bodies in aged normal controls. Cytoplasmic inclusions in neurons and glial cells were unreactive for SIGMAR1. In cultured cells, immunocytofluorescent study showed that leptomycin B and thapsigargin were shown to sequester SIGMAR1 within the nucleus, acting together with p62. This finding was also supported by immunoblot analysis. These results indicate that SIGMAR1 might shuttle between the nucleus and the cytoplasm. Neurodegenerative diseases characterized by neuronal nuclear inclusions might utilize the ER-related degradation machinery as a common pathway for the degradation of aberrant proteins.
authors: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors: Yasuo
authors: Y
authors: Miki
authors: Fumiaki
authors: F
authors: Mori
authors: Tomoya
authors: T
authors: Kon
authors: Kunikazu
authors: K
authors: Tanji
authors: Yasuko
authors: Y
authors: Toyoshima
authors: Mari
authors: M
authors: Yoshida
authors: Hidenao
authors: H
authors: Sasaki
authors: Akiyoshi
authors: A
authors: Kakita
authors: Hitoshi
authors: H
authors: Takahashi
authors: Koichi
authors: K
authors: Wakabayashi
mesh_terms: D001344:Autopsy; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017480:Receptors, sigma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000097605:Sigma-1 Receptor
chemical_list: D004268:DNA-Binding Proteins; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: chaperone; endoplasmic reticulum; neuronal nuclear inclusion; polyglutamine disease; sigma-1 receptor