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Human Molecular Genetics Advance Access published online on February 1, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl011
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 4, 2005
Revised January 30, 2006
Accepted January 30, 2006

Article

Aggregate formation and phosphorylation of Neurofilament-L Pro22 Charcot-Marie-Tooth disease mutants

Takahiro Sasaki 1, Takahiro Gotow 2, Motoko Shiozaki 2, Fumika Sakaue 1, Taro Saito 1, Jean-Pierre Julien 3, Yasuo Uchiyama 4, and Shin-ichi Hisanaga 1 *

1 Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Minami-ohsawa, Hachiohji, Tokyo 192-0397, Japan
2 Laboratory of Cell Biology, College of Nutrition, Koshien University, Takarazuka, Hyogo 665-0006, Japan
3 Centre Hospitalier de l'Universite Laval Research Center, Quebec City, Quebec, Canada
4 Department of Cell Biology and Neuroscience, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

* To whom correspondence should be addressed.
Shin-ichi Hisanaga, E-mail: hisanaga-shinichi{at}c.metro-u.ac.jp


  Abstract

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 chain (NF-L). 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 Cdk5 and ERK, which suppressed filament assembly, but phosphorylation by 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.


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