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Molecular pathogenesis of seipin/BSCL2‐related motor neuron diseases
Author(s) -
Ito Daisuke,
Suzuki Norihiro
Publication year - 2007
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21070
Subject(s) - unfolded protein response , endoplasmic reticulum , calnexin , microbiology and biotechnology , neurodegeneration , biology , motor neuron , mutant protein , ubiquitin ligase , mutant , ubiquitin , genetics , medicine , neuroscience , calreticulin , gene , disease , spinal cord
Objective Heterozygous mutations in the Seipin/BSCL2 gene have recently been identified in two autosomal dominant motor neuron diseases, distal hereditary motor neuropathy type V and Silver's syndrome. Seipin protein is reportedly a transmembrane protein localized in the endoplasmic reticulum (ER). N88S and S90L mutations of this protein disrupt its glycosylation, resulting in its aggregation, but the mechanism of neurodegeneration remains unclear. To clarify the molecular pathogenesis of seipin‐related motor neuron diseases, we expressed wild‐type and mutant seipin proteins in neuronal and nonneuronal cells. Methods and Results Coexpression of human seipin and ubiquitin showed that seipin is polyubiquitinated and its ubiquitination is enhanced by mutation. Treatment of cells with a proteasome inhibitor increased the amounts of mutant seipin in the cells, suggesting that they are degraded through the ER‐associated degradation pathway. Immunoprecipitation studies showed that mutant seipin stably binds to the ER chaperone calnexin, indicating accumulation of unfolded mutant seipin in the ER. Furthermore, expression of mutant seipin increased the level of ER stress–mediated molecules and induced apoptosis in cultured cells. Interpretation These findings demonstrate that seipin/BSCL2‐related motor neuron diseases are novel conformational diseases, and we suspect that they are tightly associated with ER stress–mediated cell death. Ann Neurol 2007;61:237–250