Pathogenesis of Myelin Protein Zero Neuropathies in Transgenic Mice

 描述（由申请人提供）：未折叠蛋白质应答（UPR）的PERK途径正在成为蛋白质稳态（蛋白质稳态）疾病的治疗靶点，包括髓鞘疾病，如多发性硬化症、脑白质营养不良和Charcot玛丽牙（CMT）神经病。我们发现PERK的下游效应物如Gadd 34是CMT 1B-S63 del小鼠中有效的治疗靶点。这些研究表明，抑制Gadd 34将蛋白质稳态重置为翻译衰减，这在S63 del神经中是有益的。然而，在这些试验性实验中，髓鞘形成的拯救是不完整的，这表明PERK可以以其他方式调节髓鞘形成。事实上，我们做出了令人惊讶的观察，即从许旺细胞中切除PERK实际上改善了髓鞘形成。这表明活化的PERK使S63 del神经中的病理学恶化。因此，PERK的这种效果可能包括规范UPR之外的目标。我们假设PERK通过扰乱UPR内的蛋白质稳态以及通过干扰UPR外的前髓鞘形成介质来干扰髓鞘形成。在这个提议中，我们将在S63 del神经中使用PERK消融来确定PERK通路可能影响髓鞘形成的各种方式。因此，我们将确定新的PERK相互作用蛋白和底物。我们还将确定PERK是否干扰钙调磷酸酶A，一种神经调节蛋白信号传导的前髓鞘介质。最后，我们将在S63 del小鼠中进行Sephin 1的临床前试验，Sephin 1是一种新型Gadd 34抑制剂，可限制ER应激期间翻译的重新激活。这些研究的结果将确定治疗PERK目标不仅在UPR内，但也将激发寻找PERK如何影响其他细胞或组织特异性功能的UPR外，并提供新的治疗目标10个或更多的CMT神经病，和其他疾病的蛋白质稳态。

 DESCRIPTION (provided by applicant): The PERK pathway of the unfolded protein response (UPR) is emerging as a therapeutic target in diseases of protein homeostasis (proteostasis), including diseases of myelin like multiple sclerosis, leukodystrophies and Charcot Marie Tooth (CMT) neuropathies. We showed that downstream effectors of PERK such as Gadd34 are valid therapeutic targets in CMT1B-S63del mice. These studies suggested that inhibiting Gadd34 resets proteostasis towards translational attenuation and this is beneficial in S63del nerves. However, rescue of myelination in these pilot experiments was incomplete, suggesting that PERK may modulate myelination in additional ways. Indeed, we made the surprising observation that ablating PERK from Schwann cells actually improved myelination. This suggests that activated PERK aggravates pathology in S63del nerves. Therefore, this effect of PERK may include targets outside of the canonical UPR. We hypothesize that PERK interferes with myelination both by perturbing proteostasis within the UPR, and also by interfering with pro- myelinating mediators outside of the UPR. In this proposal, we will use PERK ablation in S63del nerves to identify the various ways in which the PERK pathway may influence myelination. Thus, we will identify new PERK-interacting proteins and substrates. We will also determine whether PERK interferes with Calcineurin A, a pro-myelinating mediator of neuregulin signaling. Finally, we will perform a preclinical trial in S63del mice of Sephin1, a novel Gadd34 inhibitor that limits reactivation of translation during ER stress. The results of these studies will identif therapeutic PERK targets not only within the UPR, but will also motivate a search for how PERK affects other cell or tissue-specific functions outside of the UPR, and provide new therapeutic targets for 10 or more CMT neuropathies, and other diseases of proteostasis.