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.