Charcot Marie Tooth disease (CMT) is the most common inherited neuromuscular disorder. CMT presents as slowly progressive weakness beginning in the distal limbs usually in the first two decades of life. There is no treatment and for those with severe disease CMT can be disabling. Mutations in numerous genes have been associated with CMT, including mutations in P0, the most abundant protein in myelin. In the S63del CMT1B mouse, the folding of P0 is disrupted and causes a toxic gain of function. The accumulation of P0 in the endoplasmic reticulum (ER) leads to the unfolded protein response (UPR) and a demyelinating phenotype. Surprisingly, Schwann cell specific ablation of Perk, encoding a kinase activated to relieve ER stress (PERK), improves myelination in S63del mice. This improvement despite persistent ER stress led us to consider if PERK was interfering with a pathway outside of the UPR involved in myelination. We have hypothesized that calcineurin, a newly identified PERK substrate and promyelinating signal, is over activated as a result of active PERK and ER stress. Increased activation of calcineurin in S63del results in a chronic gain of function of NFATc4, an important promyelinating signal. Aberrant myelination in other neuropathies has been associated with gain of function of promyelinating signals. Using Schwann cell specific ablation of Perk (S63del/PerkSCKO) or calcineurin (S63del/CnBSCKO) in S63del mice we will study the promyelinating calcineurin pathway in normal development and disease, as well as how PERK may be perturbing this pathway when activated by the UPR. By better understanding the pathogenesis of S63del we have the potential to identify new therapeutic targets for Charcot Marie Tooth disease.
Charcot Marie Tooth (CMT) disease is an inherited neuromuscular disorder that typically affects patients in the second decade of life. There is no treatment other than supportive care and those with severe disease can quickly become wheelchair bound. The goal of this research is to improve our understanding of the mechanisms in CMT in order to provide potential targets for therapeutic interventions.
