Multiple disease‐linked myotubularin mutations cause NFL assembly defects in cultured cells and disrupt myotubularin dimerization

Abstract

J. Neurochem.(2008) 104, 1536–1552. Abstract Charcot‐Marie‐Tooth disease (CMT) is an inherited peripheral neuropathy that has been linked to mutations in multiple genes. Mutations in the neurofilament light (NFL) chain gene lead to the CMT2E form whereas mutations in the myotubularin‐related protein 2 and 13 (MTMR2 and MTMR13) genes lead to the CMT4B form. These two forms share characteristic pathological hallmarks on nerve biopsies including concentric sheaths (‘onion bulbs’) and, in at least one case, myelin loops. In addition, MTMR2 protein has been shown to interact physically with both NFL and MTMR13. Here, we present evidence that CMT‐linked mutations of MTMR2 can cause NFL aggregation in a cell line devoid of endogenous intermediate filaments, SW13vim−. Mutations in the protein responsible for X‐linked myotubular myopathy (myotubularin, MTM1) also induced NFL abnormalities in these cells. We also show that two MTMR2 mutant proteins, G103E and R283W, are unable to form dimers and undergo phosphorylation in vivo, implicating impaired complex formation in myotubularin‐related pathology.

Review of the Multiple Aspects of Neurofilament Functions, and their Possible Contribution to Neurodegeneration

“…Goryunov et al [406] showed that mutations of myotubularin-related protein 2, which lead to the CMT4B form, can cause NFL aggregation in culture cells, indicating that mutation of NFL is not necessary to induce NF aggregations in CMT. Finally, an implication of NF in demyelinating CMT cannot be excluded.…”

Dysfunctions of neuronal and glial intermediate filaments in disease

“…A second protein that interacts with NFL and has been linked to CMT is myotubularin-related protein 2 (MTMR2) (85). Mutations in MTMR2 cause a subtype of CMT, called CMT4B (Table 4), and mutant MTMR2 induces abnormal NFL assembly in transfected cells (86). It should be noted that mice lacking MTMR2 develop a CMT-like neuropathy, including several characteristics of dysmyelination (87).…”

Intermediate Filaments in Neurodegenerative Diseases

“…These data suggest that overexpression of mutant HSPB1 in neurons is sufficient to cause pathological changes in mice that are seen in patients with CMT. Mutant MTMR2 also induces abnormal NFL assembly in transfected cells [98] and mice lacking MTMR2 develop a CMT-like neuropathy, including several characteristics of dysmyelination [101]. A similar phenotype was observed following Schwann cell-specific MTMR2 inactivation, whereas neuron-specific inactivation did not provoke myelin outfoldings nor axonal defects, suggesting that loss of MTMR2 in Schwann cells, but not in motor neurons, is both sufficient and necessary to cause CMT4B neuropathy [102].…”

“…Mutations of myotubularin-related protein 2 (MTMR2) (CMT4B), heat-shock protein B1 (HSPB1) (CMT2F) or HSPB8 (CMT2L) can also cause NFL aggregation [96][97][98][99], indicating that mutation of NFs is not the only mechanism inducing their accumulation in CMT. Co-expression of Wt HSPB1 with P8R or Q333P CMT mutant NFL reduced their aggregation, induced reversal of mutant NFL aggregates and decreased mutant NFL-induced loss of motor neuron viability [100].…”