Effects of Charcot-Marie-Tooth-linked mutations of the neurofilament light subunit on intermediate filament formation.
Neurofilaments (NFs) are the major intermediate filaments (IFs) of mature neurons. They play important roles in the structure and function of axons. Recently, two mutations in the neurofilament light (NFL) subunit have been identified in families affected by Charcot-Marie-Tooth (CMT) neuropathy type 2. We have characterized the effects of these NFL mutations on the formation of IF networks using a transient transfection system. Both mutations disrupted the self-assembly of human NFL. The Q333P mutant in the rod domain of NFL also disrupted the formation of rat and human NFL/NFM heteropolymers. The phenotypes produced by the P8R mutation in the head domain of NFL were less severe. The P8R mutant NFL co-polymerized with NFM to form bundled filaments and, less often, aggregates. Our results suggest that alterations in the formation of a normal IF network in neurons elicited by these NFL mutations may contribute to the development of Charcot-Marie-Tooth neuropathy.
Perez-Olle
Raul
R
Department of Pathology, Columbia University College of Physicians & Surgeons, 630 West 168th Street, New York, NY 10032, USA.
Leung
Conrad L
CL
Liem
Ronald K H
RK
D000595:Amino Acid Sequence; D015153:Blotting, Western; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007381:Intermediate Filament Proteins / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D016900:Neurofilament Proteins / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
D007381:Intermediate Filament Proteins; D016900:Neurofilament Proteins; C044882:neurofilament protein L