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Human Molecular Genetics Advance Access published online on December 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi452
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 5, 2005
Revised December 9, 2005
Accepted December 9, 2005

Article

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

Steven Ackerley 1, Paul A. James 1, Arran Kalli 1, Sarah French 1, Kay E. Davies 1, and Kevin Talbot 1 *

1 Department of Human Anatomy and Genetics, South Parks Road, Oxford, OX1 3QX, UK

* To whom correspondence should be addressed.
Kevin Talbot, E-mail: kevin.talbot{at}clneuro.ox.ac.uk


  Abstract

Distal Hereditary Motor Neuronopathies 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.


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