CMT 1X: Attenuation of MCP-1/CCL2 expression ameliorates neuropathy in a mouse m

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Hum Mol Genet. 2010 Jun 30

Attenuation of MCP-1/CCL2 expression ameliorates neuropathy in a mouse model for

Charcot-Marie-Tooth 1X.

Groh J, Heinl K, Kohl B, Wessig C, Greeske J, Fischer S, i R.

Department of Neurology, Section of Developmental Neurobiology, University of

Wuerzburg, f-Schneider-Str. 11, D-97080 Wuerzburg, Germany.

Abstract

The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been

previously shown to be an important mediator of macrophage-related neural damage

in models of two distinct inherited neuropathies, Charcot-Marie-Tooth (CMT) 1A

and 1B.

In mice deficient in the gap junction protein Connexin 32 (Cx32def), an

established model for the X-chromosome-linked dominant form of CMT (CMT1X), we

investigated the role of the chemokine on macrophage immigration and neural

damage by crossbreeding the Cx32def mice with MCP-1 knockout mutants.

In Cx32def mutants typically expressing increased levels of MCP-1, macrophage

numbers were strongly elevated, caused by an MCP-1-mediated influx of

hematogeneous macrophages. Curiously, the complete genetic deletion of MCP-1 did

not cause reduced macrophage numbers in the nerves due to compensatory

proliferation of resident macrophages.

In contrast, and as already seen in other CMT models, heterozygous deletion of

MCP-1 led to reduced numbers of phagocytosing macrophages and an alleviation of

demyelination. Whereas alleviated demyelination was transient, axonal damage was

persistently improved and even robust axonal sprouting at 12 months was

detectable.

Other axon-related features were alleviated electrophysiological parameters,

reduced muscle denervation and atrophy, and increased muscle strength. Similar

to models for CMT1A and CMT1B, we identified MEK-ERK signalling as mediating

MCP-1 expression in Cx32-deficient Schwann cells. Blocking this pathway by the

inhibitor CI-1040 caused reduced MCP-1 expression, attenuation of macrophage

increase and amelioration of myelin-and axon-related features.

Thus, attenuation of MCP-1 upregulation by inhibiting ERK phosphorylation might

be a promising approach to treat CMT1X and other so far untreatable inherited

peripheral neuropathies in humans.