We propose to identify the intracellular pathogenesis of Myelin Protein Zero (MPZ)-related neuropathies. We have created a unique set of transgenic mice expressing various human mutations of Mpz that provide proof of principle that gain of abnormal function, deriving from diverse intracellular locations, can cause variable myelinopathy phenotypes. In one model, POS63del, we have identified the unfolded protein response (UPR). Our hypothesis is that mutant proteins that elicit myelinopathies from intracellular locations away from myelin, produce more severe neuropathy because they more generally perturb Schwann cells (kill them by apoptosis) or the program of myelin protein and lipid synthesis. Here we will exploit our models, and in particular POS63del mice, to understand how intracellular retention of mutant proteins produces demyelination. We will fully evaluate the UPR downstream mediators in POS63del nerves, and explore how the S63 alteration produces an unfolded protein. We will genetically eliminate the unfolded protein response mediator, CHOP, and characterize the effect on neuropathy to show that the UPR causes demyelinating neuropathy. We will systematically identify target genes of the CHOP transcription factor in diseased nerve, in order to test our hypothesis that the 'toxic' effect is on pivotal regulators, or multiple members of the program of myelin protein and lipid synthesis. Finally, we will explore in a novel proteasome indicator mouse whether the UPR induces inefficient proteasome function and thereby alters the physiological degradation of proteins such as PMP22, thereby inducing a PMP22 overexpression neuropathy. Charcot Marie Tooth hereditary neuropathies affect 150,000 people in the US and 3,000,000 people worldwide and account for significant lifelong disability and important economic loss. About one quarter of these neuropathies result from mutations that permit the expression of 'toxic1 proteins that interfere with the capacity of Schwann cells to form and maintain myelin in nerves. Little is known about the mechanisms of toxicity. This study will identify some of these mechanisms, and inform potential therapeutic strategies for hereditary neuropathies. The same mechanisms and strategies may also be relevant to the broad category of diseases associated with misfolded proteins including Alzheimer disease and Diabetes. ? ? ?
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