neurofilament mutation/CMT research - from the UK

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1: Hum Mol Genet 2002 Nov 1;11(23):2837-2844

Charcot-Marie-Tooth disease neurofilament mutations disrupt

neurofilament assembly and axonal transport.

Brownlees J, Ackerley S, Grierson AJ, sen NJ, Shea K, Anderton BH,

Leigh PN, Shaw CE, CC.

Department of Neuroscience and Department of Neurology, The Institute of

Psychiatry, King's College London, De Crespigny Park, Denmark Hill,

London SE5 8AF, UK.

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.