＜シンポジウム35―2＞運動ニューロン疾患の分子病態の解明と治療法開発への展望
Seipinopathy Seipin BSCL2関連運動ニューロン疾患
―神経変性における小胞体ストレスの重要性―
伊東 大介, 八木 拓也, 鈴木 則宏
慶應義塾大学医学部神経内科〔〒160―8582 東京都新宿区信濃町35〕
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.
Full Text of this Article in Japanese PDF (215K)
(臨床神経, 51：1186−1188, 2011)
key words：小胞体ストレス，運動ニューロン疾患，SPG17，セイピン，セイピノパチー
（受付日：2011年5月20日）
