Cellular events in heritable peripheral neuropathies

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Abstract Heritable demyelinating neuropathies, including Charcot-Marie-Tooth disease type 1A (CMT1A), account for a significant portion of peripheral nerve disorders leading to muscle atrophy and functional impairment. Peripheral myelin protein 22 (PMP22) is a hydrophobic integral membrane protein within Schwann cells, whose abnormal expression is associated with the majority of CMT1A cases. In most patients with demyelinating neuropathy, the PMP22 gene is duplicated, while in a smaller fraction of CMT1A and in Dejerine-Sottas Syndrome, single amino acid substitutions in PMP22 are present. Studies of nerve biopsies from neuropathic patients revealed abnormal retention of PMP22 within the Schwann cell cytosol, and the lack of correct myelin protein expression. To gain understanding into the subcellular pathogenesis of PMP22- associated neuropathies, we have characterized the posttranslational processing of PMP22 and found slowed degradation and abnormal intracellular accumulation of the protein within Schwann cells from neuropathic mice, including the point mutant Trembler J and the PMP22 overexpressor models. Since cytosolic PMP22 is only detected in nerve tissue from neuropathic and not normal mice, the abnormal intracellular accumulation of PMP22 likely contributes to the disease pathogenesis. Indeed, upon overwhelming the ubiquitin-proteasome pathway, cytosolic aggregates of PMP22 form and recruit essential Schwann cell molecules, including chaperones and myelin proteins, which alter the protein balance of the cell. Under permissive conditions, Schwann cells isolated from neonatal nerves have the ability to clear these abnormal cytosolic protein aggregates by a mechanism that is assisted by chaperones and autophagy. During the current cycle of this project, we stimulated the chaperone and autophagic responses within samples from Trembler J and PMP22 overexpressor mice, and found that the abnormal cytosolic aggregation of PMP22 can be suppressed and myelin production improved. Furthermore, we have shown that dietary stimulation of these pathways has proven beneficial to these neuropathic mice. The success of these proof-of-principle experiments sets the stage to move forward with specific pharmacologic treatment paradigms in neuropathic mice, and evaluate treatment outcome on neuromuscular function, nerve morphology and associated subcellular mechanisms. The overall aim of this project is to determine if pharmacologic enhancement of chaperones and autophagic protein degradation can slow or halt the progression of the neuropathy in young mice, and to investigate the response of samples from advanced disease stages to this approach. We will use pharmacologically characterized, known small molecules to stimulate the chaperone and autophagy pathways in young neuropathic mice and in ex vivo samples from advanced disease state mice. These studies will determine if improving the subcellular processing of PMP22 by stimulation of protein homeostatic mechanisms within Schwann cells could provide a viable approach for therapy in CMT1A and related neuropathies.