title: Normal role of the low-molecular-weight neurofilament protein in mitochondrial dynamics and disruption in Charcot-Marie-Tooth disease.
abstract: Intermediate filaments serve important structural roles, but other cellular functions are increasingly recognized. This study demonstrated normal function of the low-molecular-weight neurofilament protein (NFL) in mitochondrial dynamics and disruption in Charcot-Marie-Tooth disease (CMT) due to mutations in the Nefl gene. In motor neurons of spinal cord cultured from Nefl-knockout mice, mitochondrial length and the rate of fusion were decreased concomitant with increased motility. These parameters were normalized after expression of NFL(wt) on the Nefl(-/-) background, but not by overexpression of the profusion protein, mitofusin 2 (MFN2). The effects of CMT-causing NFL mutants bore similarities to and differences from Nefl knockout. In the early phase of toxicity before disruption of the neurofilament network, NFL(Q333P) and NFL(P8R) integrated into neurofilaments and had effects on mitochondria similar to those with Nefl knockout. The reduction of fusion rate by NFL(Q333P) was partly due to interference with the function of the profusion protein MFN2, which is mutated in CMT2A, functionally linking these forms of CMT. In the later phase of toxicity, mitochondria essentially stopped moving in neurons expressing NFL mutants, probably a consequence of cytoskeletal disruption. Overall, the data point to important functions of neurofilaments in mitochondrial dynamics as well as primary involvement in CMT2E/1F.
authors.affiliation: Montreal Neurological Institute, 3801 University St., Room 649, Montreal, QC, Canada H3A 2B4. benoit.gentil@mcgill.ca
authors.forename: Benoit J
authors.initials: BJ
authors.lastname: Gentil
authors.forename: Sandra
authors.initials: S
authors.lastname: Minotti
authors.forename: Madeleine
authors.initials: M
authors.lastname: Beange
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
authors.forename: Heather D
authors.initials: HD
authors.lastname: Durham
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D008970:Molecular Weight; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors
chemical_list: D016900:Neurofilament Proteins; C044882:neurofilament protein L; D049452:Green Fluorescent Proteins; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse