Molecular pathogenesis of Seipin/BSCL2-related motor neuron diseases

Daisuke Ito, Norihiro Suzuki

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)237-250
Number of pages14
JournalAnnals of Neurology
Volume61
Issue number3
DOIs
Publication statusPublished - 2007 Mar

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Motor Neuron Disease
Endoplasmic Reticulum
Endoplasmic Reticulum Stress
Mutation
Endoplasmic Reticulum-Associated Degradation
Calnexin
Proteins
Proteasome Inhibitors
Ubiquitination
Mutant Proteins
Ubiquitin
Glycosylation
Immunoprecipitation
Cultured Cells
Cell Death
Apoptosis
Genes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Molecular pathogenesis of Seipin/BSCL2-related motor neuron diseases. / Ito, Daisuke; Suzuki, Norihiro.

In: Annals of Neurology, Vol. 61, No. 3, 03.2007, p. 237-250.

Research output: Contribution to journalArticle

Ito, Daisuke ; Suzuki, Norihiro. / Molecular pathogenesis of Seipin/BSCL2-related motor neuron diseases. In: Annals of Neurology. 2007 ; Vol. 61, No. 3. pp. 237-250.
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