CMT 2E: Mitochondrial and Axonal Abnormalities Precede Disruption of the Neurofi

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J Neuropathol Exp Neurol. 2009 May 18.

Mitochondrial and Axonal Abnormalities Precede Disruption of the Neurofilament

Network in a Model of Charcot-Marie-Tooth Disease Type 2E and Are Prevented by

Heat Shock Proteins in a Mutant-Specific Fashion.

Tradewell ML, Durham HD, Mushynski WE, Gentil BJ.

From the Department of Neurology/Neurosurgery and Montreal Neurological

Institute (MLT, HDD, BJG); and Department of Biochemistry (WEM, BJG), McGill

University, Montreal, Quebec, Canada.

Mutations in NEFL encoding the light neurofilament subunit (NFL) cause

Charcot-Marie-Tooth disease type 2E (CMT2E), which affects both motor and

sensory neurons. We expressed the disease-causing mutants NFL and NFL in motor

neurons of dissociated spinal cord-dorsal root ganglia and demonstrated that

they are incorporated into the preexisting neurofilament network but eventually

disrupt neurofilaments without causing significant motor neuron death.

Importantly, rounding of mitochondria and reduction in axonal diameter occurred

before disruption of the neurofilament network, indicating that mitochondrial

dysfunction contributes to the pathogenesis of CMT2E, as well as to CMT caused

by mitofusin mutations.

Heat shock proteins (HSPs) are involved in the formation of the neurofilament

network and in protecting cells from misfolded mutant proteins. Cotransfection

of HSPB1 with mutated NEFL maintained the neurofilament network, axonal

diameter, and mitochondrial length in motor neurons expressing NFL, but not NFL.

Conversely, HSPA1 cotransfection was effective in motor neurons expressing NFL,

but not NFL. Thus, there are NFL mutant-specific differences in the ability of

individual HSPs to prevent neurofilament abnormalities, reduction in axonal

caliber, and disruption of mitochondrial morphology in motor neurons.

These results suggest that HSP inducers have therapeutic potential for CMT2E but

that their efficacy would depend on the profile of HSPs induced and the type of

NEFL mutation.