Loss of YAP in Schwann cells improves HNPP pathophysiology.

Rapid nerve conduction in the peripheral nervous system (PNS) is facilitated by the multilamellar myelin sheath encasing many axons of peripheral nerves. Charcot-Marie-Tooth type 1A (CMT1A), and hereditary neuropathy with liability to pressure palsy (HNPP) are common demyelinating inherited peripheral neuropathies and are caused by mutations in the peripheral myelin protein 22 (PMP22) gene. Duplication of PMP22 leads to its overexpression and causes CMT1A, while its deletion results in PMP22 under expression and causes HNPP. Here, we investigated novel targets for modulating the protein level of PMP22 in HNPP. We found that genetic attenuation of the transcriptional coactivator Yap in Schwann cells reduces p-TAZ levels, increased TAZ activity, and increases PMP22 in peripheral nerves. Based on these findings, we ablated Yap alleles in Schwann cells of the Pmp22-haploinsufficient mouse model of HNPP and identified fewer tomacula on morphological assessment and improved nerve conduction in peripheral nerves. These findings suggest YAP modulation may be a new avenue for treatment of HNPP.

PMP2 regulates myelin thickening and ATP production during remyelination.

It is well established that axonal Neuregulin 1 type 3 (NRG1t3) regulates developmental myelin formation as well as EGR2-dependent gene activation and lipid synthesis. However, in peripheral neuropathy disease context, elevated axonal NRG1t3 improves remyelination and myelin sheath thickness without increasing Egr2 expression or activity, and without affecting the transcriptional activity of canonical myelination genes. Surprisingly, Pmp2, encoding for a myelin fatty acid binding protein, is the only gene whose expression increases in Schwann cells following overexpression of axonal NRG1t3. Here, we demonstrate PMP2 expression is directly regulated by NRG1t3 active form, following proteolytic cleavage. Then, using a transgenic mouse model overexpressing axonal NRG1t3 (NRG1t3OE) and knocked out for PMP2, we demonstrate that PMP2 is required for NRG1t3-mediated remyelination. We demonstrate that the sustained expression of Pmp2 in NRG1t3OE mice enhances the fatty acid uptake in sciatic nerve fibers and the mitochondrial ATP production in Schwann cells. In sum, our findings demonstrate that PMP2 is a direct downstream mediator of NRG1t3 and that the modulation of PMP2 downstream NRG1t3 activation has distinct effects on Schwann cell function during developmental myelination and remyelination.