Heritable demyelinating neuropathies, including Charcot-Marie-Tooth disease type 1A (CMT1 A), account for a significant portion of peripheral nerve disorders leading to muscle atrophy and functional impairment. Peripheral myelin protein 22 (PMP22) is a 22kD hydrophobic integral membrane protein, whose abnormal expression is associated with the majority of CMT1A cases. In most demyelinating neuropathy patients, the PMP22 gene is duplicated, while in a smaller fraction of CMT1A and Dejerine-Sottas Syndrome patients, single amino acid substitutions in PMP22 are present. Studies of CMT1A nerve biopsies revealed abnormal retention of PMP22 inside the Schwann cell cytosol, indicating altered protein trafficking and degradation. During the current cycle of this grant, we detected cytosolic accumulation and slowed degradation of PMP22 in Schwann cells of Trembler J (TrJ) and PMP22 overexpressor mouse models of CMT. Cytosolic aggregates of the abnormal PMP22 recruit essential Schwann cell molecules, including chaperones, myelin proteins and constituents of the ubiquitin-proteasome pathway, which alters the protein balance of the cell. Under permissive conditions, Schwann cells have the ability to clear these abnormal cytosolic protein aggregates by a mechanism that is assisted by autophagy and chaperones. These observations indicate that Schwann cells possess the endogenous ability to clear the misfolded PMP22, however these pathways might become overwhelmed with disease progression and age. The overall aim of this project is to determine if by stimulating the autophagic and chaperone responses of Schwann cells from Trembler J and PMP22 overproducer mice, the abnormal cytosolic aggregation of PMP22 can be suppressed or reversed. We will use well-characterized pharmacologic agents to stimulate these pathways and study the response of the neuropathy Schwann cells in vitro. In parallel, we will test if in vivo modulation of these pathways in neuropathy mice can improve motor performance and resolve the subcellular abnormalities. These studies will determine if modulating the intracellular fate of PMP22 in Schwann cells of neuropathy mice could provide a viable approach for therapy.
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