title: Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport.
abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system, and mutations in neurofilaments have been linked to some forms of CMT. Neurofilaments are the major intermediate filaments of neurones, but the mechanisms by which the CMT mutations induce disease are not known. Here, we demonstrate that CMT mutant neurofilaments disrupt both neurofilament assembly and axonal transport of neurofilaments in cultured mammalian cells and neurones. We also show that CMT mutant neurofilaments perturb the localization of mitochondria in neurones. Accumulations of neurofilaments are a pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and diabetic neuropathy. Our results demonstrate that aberrant neurofilament assembly and transport can induce neurological disease, and further implicate defective neurofilament metabolism in the pathogenesis of human neurodegenerative diseases.
authors.affiliation: Department of Neuroscience, The Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Brownlees
authors.forename: Steven
authors.initials: S
authors.lastname: Ackerley
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grierson
authors.forename: Nick J O
authors.initials: NJ
authors.lastname: Jacobsen
authors.forename: Kerry
authors.initials: K
authors.lastname: Shea
authors.forename: Brian H
authors.initials: BH
authors.lastname: Anderton
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
mesh_terms: D000818:Animals; D001370:Axonal Transport; D001693:Biological Transport, Active; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D016900:Neurofilament Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010957:Plasmids; D016133:Polymerase Chain Reaction; D051381:Rats; D014162:Transfection
chemical_list: D017931:DNA Primers; D008164:Luminescent Proteins; D016900:Neurofilament Proteins; D049452:Green Fluorescent Proteins