[BSCL2-related neurologic disorders/seipinopathy: endoplasmic reticulum stress in neurodegeneration].

The Seipin/BSCL2 gene was originally identified as a loss-of-function gene for congenital generalized lipodystrophy type 2, a condition characterized by severe lipoatrophy, insulin resistance, and hypertriglyceridemia. Whereas gain-of-toxic-function mutations (namely, mutations N88S and S90L) in the seipin gene have been identified in autosomal dominant motor neuron diseases such as Silver syndrome/spastic paraplegia 17 (SPG17) and distal hereditary motor neuropathy type V. Detailed phenotypic analyses have revealed that upper motor neurons, lower motor neurons and peripheral motor axons are variously affected in patients with these mutations. We recently showed that the N88S and S90L mutations disrupt the N-glycosylation motif, enhance ubiquitination, and appear to result in proteins that are improperly folded, leading to accumulation of the mutant protein in the endoplasmic reticulum (ER). We also showed that expression of mutant in cultured cells activates the UPR pathway and induces cell death, suggesting that seipinopathy is tightly associated with ER stress, which has recently been reported to be associated with other neurodegenerative diseases. Further study of the pathological mechanisms of the mutant forms of seipin may lead to important new insights into motor neuron diseases, including other spastic paraplegia diseases and amyotrophic lateral sclerosis.