ササキ　タカヒロ   Sasaki Takahiro   佐々木　孝寛    所属   医学部 医学科（東京女子医科大学病院）    職種   助教
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Aggregate formation and phosphorylation of neurofilament-L Pro22 Charcot-Marie-Tooth disease mutants.
掲載誌名	正式名：Human molecular genetics 略　 称：Hum Mol Genet ISSNコード：09646906/09646906
掲載区分	国外
巻・号・頁	15(6),pp.943-52
国際共著	国際共著
著者・共著者	Sasaki Takahiro†, Gotow Takahiro, Shiozaki Motoko, Sakaue Fumika, Saito Taro, Julien Jean-Pierre, Uchiyama Yasuo, Hisanaga Shin-Ichi
担当区分	筆頭著者
発行年月	2006/03
概要	Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral nerve disorder. The causative gene for axonal type CMT2E has been identified as neurofilament light (NF-L) chain. Using cultured cells and in vitro assays, we analyzed the filament formation ability of Pro22 CMT mutant proteins of NF-L, P22S and P22T. NF-L Pro22 mutant proteins formed large aggregates in SW13- cells and cortical neurons and assembled into short twisty threads thinner than 10 nm filaments in vitro. Those threads associated with each other at their ends and entangled into large aggregates, also abnormalities, were detected at steps in oligomer formation. Pro22 mutations abolished Thr21 phosphorylation by cyclin-dependent kinase 5 and external signal regulated kinase, which suppressed filament assembly, but phosphorylation by protein kinase A (PKA) inhibited aggregate formation in vitro and alleviated aggregates in cortical neurons. These results indicate that the Pro22 CMT mutation induces abnormal filament aggregates by disrupting proper oligomer formation and the aggregates are mitigated by phosphorylation with PKA, which makes it a viable target for the development for therapeutics.
DOI	10.1093/hmg/ddl011
PMID	16452125