Human Molecular Genetics Advance Access originally published online on February 1, 2006
Human Molecular Genetics 2006 15(6):943-952; doi:10.1093/hmg/ddl011
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Aggregate formation and phosphorylation of neurofilament-L Pro22 Charcot–Marie–Tooth disease mutants
1Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Minami-ohsawa, Hachiohji, Tokyo 192-0397, Japan, 2Laboratory of Cell Biology, College of Nutrition, Koshien University, Takarazuka, Hyogo 665-0006, Japan, 3Centre Hospitalier de l'Universite Laval Research Center, Quebec City, Quebec, Canada and 4Department of Cell Biology and Neuroscience, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
* To whom correspondence should be addressed. Tel: +81 426772577; Fax: +81 426772559; Email: hisanaga-shinichi{at}c.metro-u.ac.jp
Received December 4, 2005; Accepted January 30, 2006
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.
Present address: Nathan Kline Institute, New York University School of Medicine, Orangeburg, NY 10962, USA.
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