Abstract
Charcot-Marie-Tooth disease type 4C (CMT4C) is one of the commonest autosomal recessive inherited peripheral neuropathies and is associated with mutations in the Rab11 effector, SH3TC2. Disruption of the SH3TC2–Rab11 interaction is the molecular abnormality underlying this disease. However, why SH3TC2 mutations cause an isolated demyelinating neuropathy remains unanswered. Here we show that SH3TC2 is an exclusive Schwann cell protein expressed late in myelination and is downregulated following denervation suggesting a functional role in myelin sheath maintenance. We support our data with an evolutionary cell biological analysis showing that the SH3TC2 gene, and its paralogue SH3TC1, are derived from an ancestral homologue, the duplication of which occurred in the common ancestor of jawed vertebrates, coincident with the appearance of Schwann cells and peripheral axon myelination. Furthermore, we report that SH3TC2 associates with integrin-α6, suggesting that aberrant Rab11-dependent endocytic trafficking of this critical laminin receptor in myelinated Schwann cells is connected to the demyelination seen in affected nerves. Our study therefore highlights the inherent evolutionary link between SH3TC2 and peripheral nerve myelination, pointing also towards a molecular mechanism underlying the specific demyelinating neuropathy that characterizes CMT4C.
Highlights
Progressive degeneration of peripheral nerves is the pathological hallmark of the Charcot-Marie-Tooth diseases (CMT), the most common inherited neuromuscular disorder
We report that SH3TC2 associates with the laminin receptor, integrin-α6, providing a mechanistic link between SH3TC2 and the structural maintenance of the myelin sheath
We found that the SH3TC2 gene is present in taxa from humans to bony fish (Actinopterygii), lending substantial support to our hypothesis that the SH3TC2 gene emerged at the same time as Schwann cellmediated peripheral nerve myelination (Fig. 6A and Supplementary Fig. 6)
Summary
Progressive degeneration of peripheral nerves is the pathological hallmark of the Charcot-Marie-Tooth diseases (CMT), the most common inherited neuromuscular disorder. In keeping with this anatomical dichotomy, CMT can be classified into ‘demyelinating’ or ‘axonal’ forms, reflecting the main sites of pathology as the Schwann cell or axon, respectively [3]. Schwann cell myelination of axons is highly regulated and is characterized by the sequential segregation of ion-channels and scaffolding proteins to form specialized domains along the peripheral nerve such as the node of Ranvier, juxtaparanode and the paranodal region. Disruption of these regions can lead to peripheral nerve dysfunction and a peripheral neuropathy [4]
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