Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases
Version of Record online: 23 MAR 2007
Copyright © 2007 American Neurological Association
Annals of Neurology
Volume 61, Issue 3, pages 237–250, March 2007
How to Cite
Ito, D. and Suzuki, N. (2007), Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann Neurol., 61: 237–250. doi: 10.1002/ana.21070
- Issue online: 23 MAR 2007
- Version of Record online: 23 MAR 2007
- Manuscript Accepted: 24 NOV 2006
- Manuscript Received: 22 OCT 2006
- Manuscript Revised: 22 OCT 2006
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.
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