Sunday, May 5, 2024
5/5/2024
Charcot-Marie-Tooth disease (CMT) is a group of disorders and the most common inherited peripheral neuropathy with a prevalence of 1:2500. Approximately 1,000 small mutations (missense, nonsense, small deletion or insertion, splice alterations) in more than 40 genes are responsible for CMT. CMT severely impacts the is orthopedic quality of life for patients and no effective prevention or cure for CMT, and patient care is limited to physical and occupational therapies, devices, and pain relief, which is often suboptimal. accounts for significant lifelong disability and important economic loss. There CMT type 1 is a demyelinating peripheral neuropathy characterized by reduced motor nerve conduction velocities (less than 38 m/s) and segmental demyelination and remyelination with onion bulb formations on nerve biopsy. Despite the different subtypes of CMT associated with distinct genetic causes and pathogenetic mechanisms, all forms of CMT1 eventually converge on the loss of myelinated nerve fibers. Thus, a common approach based on enhancing myelination in diseased nerves without exacerbating myelin damages must be identified to provide widely effective therapy for the array of CMT neuropathies. We previously showed that enhancing axonal NRG1tIII signaling increases fatty acid levels in myelin, improves myelination and nerve function in mouse models for inherited demyelinating neuropathy, through an alternative EGR2-independent pathway. Notably, we found that PMP2, a fatty acid-binding protein is uniquely up-regulated downstream NRG1tIII overexpression in Schwann cells. Our central hypothesis of this proposal is that overexpression of the fatty acid-binding protein PMP2 is a downstream promyelinating mediator of NRG1tIII- mediated hypermyelination and that sustained overexpression of PMP2 is sufficient to improve myelin formation, without exacerbating myelin damages. We have now compelling preliminary evidence that PMP2 overexpression in Schwann cells enhances the uptake of fatty acid, increases ATP production, and is beneficial to Schwann cell myelination and remyelination. Thus, we propose to determine if PMP2 overexpression is a suitable strategy to improve myelination defects in inherited peripheral demyelinating neuropathy (P0S63del), which of PMP2 functions are beneficial to improve myelin formation, and how Pmp2 expression is being regulated. The new mechanistic insights on PMP2 overexpression enhancing myelination we will gain from this work are in line with NINDS objective seeking fundamental knowledge about the nervous system that may facilitate the development of future interventions to reduce the disease burden in patients with peripheral neuropathies.
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