Mutations in MTMR2, the myotubularin-related 2 gene, cause autosomal recessive Charcot-Marie-Tooth (CMT) type 4B1, a demyelinating neuropathy with myelin outfolding and azoospermia. MTMR2 encodes a ubiquitously expressed phosphatase whose preferred substrate is phosphatidylinositol (3,5)-biphosphate, a regulator of membrane homeostasis and vesicle transport. We generated Mtmr2-null mice, which develop progressive neuropathy characterized by myelin outfolding and recurrent loops, predominantly at paranodal myelin, and depletion of spermatids and spermatocytes from the seminiferous epithelium, which leads to azoospermia. Disruption of Mtmr2 in Schwann cells reproduces the myelin abnormalities. We also identified a novel physical interaction in Schwann cells, between Mtmr2 and discs large 1 (Dlg1)/synapse-associated protein 97, a scaffolding molecule that is enriched at the node/paranode region. Dlg1 homologues have been located in several types of cellular junctions and play roles in cell polarity and membrane addition. We propose that Schwann cell–autonomous loss of Mtmr2–Dlg1 interaction dysregulates membrane homeostasis in the paranodal region, thereby producing outfolding and recurrent loops of myelin.

Mutations in MTMR2, the myotubularin-related 2 gene, cause autosomal recessive Charcot-Marie-Tooth type 4B1 (CMT4B1). This disorder is characterized by childhood onset of weakness and sensory loss, severely decreased nerve conduction velocity, demyelination in the nerve with myelin outfoldings, and severe functional impairment of affected patients, mainly resulting from loss of myelinated fibers in the nerve. We recently generated Mtmr2-null(neo) mice, which show a dysmyelinating neuropathy with myelin outfoldings, thus reproducing human CMT4B1. Mtmr2 is detected in both Schwann cells and neurons, in which it interacts with discs large 1/synapse-associated protein 97 and neurofilament light chain, respectively. Here, we specifically ablated Mtmr2 in either Schwann cells or motor neurons. Disruption of Mtmr2 in Schwann cells produced a dysmyelinating phenotype very similar to that of the Mtmr2-null(neo) mouse. Disruption of Mtmr2 in motor neurons does not provoke myelin outfoldings nor axonal defects. We propose that loss of Mtmr2 in Schwann cells, but not in motor neurons, is both sufficient and necessary to cause CMT4B1 neuropathy. Thus, therapeutical approaches might be designed in the future to specifically deliver the Mtmr2 phospholipid phosphatase to Schwann cells in affected nerves.

The presence of activated microglia in the spinal cord of amyotrophic lateral sclerosis (ALS) patients is usually accompanied by inflammatory biochemical changes, but these are largely unexplored. Monocyte chemoattractant protein-1 (MCP-1) is critical for recruitment of inflammatory cells of monocytic lineage after inflammation or injury to the central nervous system. MCP-1 concentrations were measured by an enzyme-linked immunosorbent assay in the cerebrospinal fluid (CSF) and the serum of 27 patients with ALS and 30 patients with noninflammatory neurological diseases. In ALS, circulating MCP-1 levels were significantly increased in the serum and particularly in the CSF. Immunoreactivity for MCP-1 in ALS spinal cord was detected mostly in astrocytes but also in microglia, neurons, and within the vasculature of the cord. Our findings suggest a role for MCP-1 as an important molecular mediator of the injury response in ALS.