Neurofilament-L Pro22 in CMT mutants: aggregate formation + phosphorylation

[Guest guest]

Hum Mol Genet. 2006 Feb 1

Aggregate formation and phosphorylation of Neurofilament-L Pro22

Charcot-Marie-Tooth disease mutants.

Sasaki T, Gotow T, Shiozaki M, Sakaue F, Saito T, n JP, Uchiyama

Y, Hisanaga SI.

Department of Biological Sciences, Graduate School of Science, Tokyo

Metropolitan University, Minami-ohsawa, Hachiohji, Tokyo 192-0397,

Japan.

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.