title: A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes.
abstract: Distal hereditary motor neuronopathies (dHMNs) are a clinically and genetically heterogeneous group of disorders in which motor neurons selectively undergo age-dependant degeneration. Mutations in the small heat-shock protein HSPB1 (HSP27) are responsible for one form of dHMN. In this study, we have analysed the effect of expressing a form of mutant HSPB1 in primary neuronal cells in culture. Mutant (P182L) but not wild-type HSPB1 led to the formation of insoluble intracellular aggregates and to the sequestration in the cytoplasm of selective cellular components, including neurofilament middle chain subunit (NF-M) and p150 dynactin. These findings suggest a possible pathogenic mechanism for HSPB1 whereby the mutation may lead to preferential motor neuron loss by disrupting selective components essential for axonal structure and transport.
authors.affiliation: Department of Human Anatomy and Genetics, South Parks Road, Oxford OX1 3QX, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Ackerley
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.forename: Arran
authors.initials: A
authors.lastname: Kalli
authors.forename: Sarah
authors.initials: S
authors.lastname: French
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
mesh_terms: D001370:Axonal Transport / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D017931:DNA Primers; D000072159:Dynactin Complex; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones; D016472:Motor Neuron Disease / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D016900:Neurofilament Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D000072159:Dynactin Complex; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D016900:Neurofilament Proteins; C061195:neurofilament protein M