MCP-1/CCL2 Modifies Axon Properties in a PMP22-Overexpressing Mouse Model for Charcot-Marie-Tooth 1A Neuropathy

Abstract

Charcot-Marie-Tooth 1A (CMT1A) neuropathy, the most common inherited peripheral neuropathy, is primarily caused by a gene duplication for the peripheral myelin protein-22 (PMP22). In an accordant mouse model, we investigated the role of monocyte chemoattractant protein-1 (MCP-1/CCL2) as a regulator of nerve macrophages and neural damage including axonopathy and demyelination. By generating PMP22tg mice with reduced levels or lack of MCP-1/CCL2, we found that MCP-1/CCL2 is involved in the increase of macrophages in mutant nerves. PMP22tg mice with wild-type levels of MCP-1/CCL2 showed strong macrophage increase in the diseased nerves, whereas either 50% reduction or total absence of MCP-1/CCL2 led to a moderate or a strong reduction of nerve macrophages, respectively. Interestingly, MCP-1/CCL2 expression level and macrophage numbers were correlated with features indicative of axon damage, such as maldistribution of K+ channels, reduced compound muscle action potentials, and muscle weakness. Demyelinating features, however, were most highly reduced when MCP-1/CCL2 was diminished by 50%, whereas complete lack of MCP-1/CCL2 showed an intermediate demyelinating phenotype. We also identified the MEK1/2-ERK1/2-pathway as being involved in MCP-1/CCL2 expression in the Schwann cells of the CMT1A model. Our data show that, in a CMT1A model, MCP-1/CCL2 activates nerve macrophages, mediates both axon damage and demyelination, and may thus be a promising target for therapeutic approaches.

Clinical progression in Charcot–Marie-Tooth disease type 1A duplication: clinico-electrophysiological and MRI longitudinal study of a family

“…Our proband patient showed gradual progression after more than two decades of stabilization. Furthermore, in a PMP22-overexpressing mouse model for CMT1A, there is evidence that the chemokine monocyte chemoattractant protein-1 activates nerve macrophages and mediates both axonal damage and demyelination [22]. It is worth noting the divergent temporal evolution of imaging lesions of anterior femoral musculature described here: at initial study marked edema and mild fatty atrophy were noted, whereas 3 years later fatty atrophy predominated over edema.…”

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

“…The CMT1A-associated increases in ErbB2 and ErbB3 levels would be predicted to cause over-activation of ErbB receptor signaling, leading to abnormal downstream signaling in Schwann cells. In support of this possibility, increased Erk signaling was found in CMT1A mouse [107] and rat [27] models, and reduced Akt signaling was observed in CMT1A rat model [27]. Together, these findings raise an intriguing possibility that dysregulated ErbB2/ErbB3 receptor trafficking and signaling may be involved in CMT1A pathogenesis, a hypothesis which requires investigation by future experiments.…”

“…For example, ErbB receptor kinase inhibitor PKI 166 is able to abrogate Mycobacterium leprae -induced ErbB2 and Erk signaling over-activation and demyelination in mice [33]. Mek inhibitor, such as CI-1040 and U0126, has been shown to reduce the augmented Erk signaling and demyelination phenotype in rodent models of CMT1A [27, 107] and CMT1X [112]. In addition, agents such as geldanamycin [121] and ErbB receptor-specific monoclonal antibodies [122–124] that facilitate ErbB receptor endocytosis and degradation could be explored in preclinical studies for treating certain forms of CMT with elevated ErbB levels and augmented Erk signaling (Table 2).…”

Sustained MAPK/ERK Activation in Adult Schwann Cells Impairs Nerve Repair

“…However, similar abnormalities in nonmyelinating axons have been described in animal models of the hereditary neuropathies CMT1A and CMT4C (Robertson et al, 2002;Houlden et al, 2009). Interestingly, activated MEK/ERK has been reported in such models before axonal damage (Kohl et al, 2010;Fledrich et al, 2014).…”