title: Charcot-Marie-Tooth causing HSPB1 mutations increase Cdk5-mediated phosphorylation of neurofilaments.
abstract: Mutations in the small heat shock protein HSPB1 (HSP27) are a cause of axonal Charcot-Marie-Tooth neuropathy (CMT2F) and distal hereditary motor neuropathy. To better understand the effect of mutations in HSPB1 on the neuronal cytoskeleton, we stably transduced neuronal cells with wild-type and mutant HSPB1 and investigated axonal transport of neurofilaments (NFs). We observed that mutant HSPB1 affected the binding of NFs to the anterograde motor protein kinesin, reducing anterograde transport of NFs. These deficits were associated with an increased phosphorylation of NFs and cyclin-dependent kinase Cdk5. As Cdk5 mediates NF phosphorylation, inhibition of Cdk5/p35 restored NF phosphorylation level, as well as NF binding to kinesin in mutant HSPB1 neuronal cells. Altogether, we demonstrate that HSPB1 mutations induce hyperphosphorylation of NFs through Cdk5 and reduce anterograde transport of NFs.
authors.affiliation: Department of Molecular Genetics, VIB and University of Antwerp, 2610 Antwerpen, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Holmgren
authors.forename: Delphine
authors.initials: D
authors.lastname: Bouhy
authors.forename: Vicky
authors.initials: V
authors.lastname: De Winter
authors.forename: Bob
authors.initials: B
authors.lastname: Asselbergh
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Timmermans
authors.forename: Joy
authors.initials: J
authors.lastname: Irobi
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
mesh_terms: D001370:Axonal Transport / Q000235:genetics; D001369:Axons / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins; D006801:Humans; D047468:Immunoprecipitation; D016547:Kinesins / Q000378:metabolism; D018832:Molecular Chaperones; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D014162:Transfection / Q000379:methods
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016900:Neurofilament Proteins; D051360:Cyclin-Dependent Kinase 5; D016547:Kinesins