Journal Article

Attenuation of MCP-1/CCL2 expression ameliorates neuropathy in a mouse model for Charcot–Marie–Tooth 1X

Janos Groh, Kristina Heinl, Bianca Kohl, Carsten Wessig, Juliane Greeske, Stefan Fischer and Rudolf Martini

in Human Molecular Genetics

Volume 19, issue 18, pages 3530-3543
Published in print September 2010 | ISSN: 0964-6906
Published online June 2010 | e-ISSN: 1460-2083 | DOI:
Attenuation of MCP-1/CCL2 expression ameliorates neuropathy in a mouse model for Charcot–Marie–Tooth 1X

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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 in 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 haematogenous 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 was detectable at 12 months. 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 alterations. 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.

Journal Article.  7901 words.  Illustrated.

Subjects: Genetics and Genomics

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