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Human Molecular Genetics, 2002, Vol. 11, No. 23 2837-2844
© 2002 Oxford University Press

Charcot–Marie–Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport

Janet Brownlees, Steven Ackerley, Andrew J. Grierson{dagger}, Nick J.O. Jacobsen, Kerry Shea, Brian H. Anderton, P. Nigel Leigh, Christopher E. Shaw and Christopher C.J. Miller*

Department of Neuroscience and Department of Neurology, The Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK

Received June 20, 2002; Accepted August 20, 2002

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.

* To whom correspondence should be addressed at: Department of Neuroscience, PO Box P037, The Institute of Psychiatry, Kings College London, De Crespigny Park, Denmark Hill. London SE5 8AF, UK. Tel: +44 2078480393; Fax: +44 2077080017; Email: chris.miller{at}iop.kcl.ac.uk

{dagger} Present address: Academic Neurology Unit, Medical School, University of Sheffield, Sheffield S10 2RX, UK.


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