Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases.

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.