Mutations in the neurofilament light gene linked to CMT cause defects in transpo

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J Neurochem. 2005 May;93(4):861-74.

Mutations in the neurofilament light gene linked to Charcot-Marie-

Tooth disease cause defects in transport.

-Olle R, -Toledano MA, Goryunov D, Cabrera-Poch N, Stefanis

L, Brown K, Liem RK.

Department of Pathology, Columbia University Medical Center, New

York, New York, USA.

Abstract Neurofilament light gene mutations have been linked to a

subset of patients with Charcot-Marie-Tooth disease, the most common

inherited motor and sensory neuropathy. We have previously shown that

Charcot-Marie-Tooth-linked mutant neurofilament light assembles

abnormally in non-neuronal cells. In this study, we have

characterized the effects of expression of mutant neurofilament light

proteins on axonal transport in a neuronal cell culture model. We

demonstrated that the Charcot-Marie-Tooth-linked neurofilament light

mutations: (i) affect the axonal transport of mutant neurofilaments;

(ii) have a dominant-negative effect on the transport of wild-type

neurofilaments; (iii) affect the transport of mitochondria and the

anterograde axonal transport marker human amyloid precursor protein;

(iv) result in alterations of retrograde axonal transport and (v)

cause fragmentation of the Golgi apparatus. Increased neuritic

degeneration was observed in neuronal cells overexpressing

neurofilament light mutants. Our results suggest that these

generalized axonal transport defects could be responsible for the

neuropathy in Charcot-Marie-Tooth disease.