Unfolded protein response, treatment and CMT1B.

CMT1B is the second most frequent autosomal dominant inherited neuropathy and is caused by assorted mutations of the myelin protein zero (MPZ) gene. MPZ mutations cause neuropathy gain of function mechanisms that are largely independent MPZs normal role of mediating myelin compaction. Whether there are only a few or multiple pathogenic mechanisms that cause CMT1B is unknown. Arg98Cys and Ser63Del MPZ are two CMT1B causing mutations that have been shown to cause neuropathy in mice at least in part by activating the unfolded protein response (UPR). We have recently treated Arg98Cys mice with derivatives of curcumin that improved the neuropathy and reduced UPR activation.(1) Future studies will address whether manipulating the UPR will be a common or rare strategy for treating CMT1B or other forms of inherited neuropathies.