Cellular events in heritable peripheral neuropathies

描述(申请人提供)：遗传性脱髓鞘神经病，包括Charcot-Marie-Tooth病1A型(CMT1A)，在导致肌肉萎缩和功能障碍的周围神经疾病中占很大比例。外周髓鞘蛋白22(PMP22)是一种22kD的疏水性完整膜蛋白，其异常表达与大多数CMT1A病例有关。在大多数脱髓鞘神经病患者中，PMP22基因是复制的，而在一小部分CMT1A和DeJerine-Sottas综合征患者中，存在PMP22的单一氨基酸替换。对CMT1A神经活检的研究发现，PMP22异常滞留在雪旺细胞胞浆中，表明蛋白质运输和降解发生了变化。在这项赠款的当前周期中，我们检测到颤抖者J(TRJ)和PMP22过表达的小鼠模型CMT的雪旺细胞中PMP22的胞浆积聚和降解放缓。异常PMP22的胞浆聚集物招募必要的雪旺细胞分子，包括伴侣、髓鞘蛋白和泛素-蛋白酶体途径的成分，从而改变细胞的蛋白质平衡。在允许的条件下，雪旺细胞有能力通过自噬和伴侣蛋白辅助的机制清除这些异常的胞浆蛋白聚集体。这些观察表明，雪旺细胞具有清除错误折叠的PMP22的内源性能力，但这些途径可能会随着疾病的进展和年龄的增长而变得不堪重负。该项目的总体目标是确定是否可以通过刺激颤栗J和PMP22过度产生的小鼠的雪旺细胞的自噬和伴侣反应，抑制或逆转PMP22的异常胞浆聚集。我们将使用具有良好特性的药理学药物来刺激这些通路，并在体外研究神经病变雪旺细胞的反应。同时，我们将测试在神经病小鼠体内对这些通路的调节是否可以改善运动能力并解决亚细胞异常。这些研究将确定调节神经病变小鼠雪旺细胞中PMP22的细胞内命运是否可以提供一种可行的治疗方法。

DESCRIPTION (provided by applicant): Heritable demyelinating neuropathies, including Charcot-Marie-Tooth disease type 1A (CMT1 A), account for a significant portion of peripheral nerve disorders leading to muscle atrophy and functional impairment. Peripheral myelin protein 22 (PMP22) is a 22kD hydrophobic integral membrane protein, whose abnormal expression is associated with the majority of CMT1A cases. In most demyelinating neuropathy patients, the PMP22 gene is duplicated, while in a smaller fraction of CMT1A and Dejerine-Sottas Syndrome patients, single amino acid substitutions in PMP22 are present. Studies of CMT1A nerve biopsies revealed abnormal retention of PMP22 inside the Schwann cell cytosol, indicating altered protein trafficking and degradation. During the current cycle of this grant, we detected cytosolic accumulation and slowed degradation of PMP22 in Schwann cells of Trembler J (TrJ) and PMP22 overexpressor mouse models of CMT. Cytosolic aggregates of the abnormal PMP22 recruit essential Schwann cell molecules, including chaperones, myelin proteins and constituents of the ubiquitin-proteasome pathway, which alters the protein balance of the cell. Under permissive conditions, Schwann cells have the ability to clear these abnormal cytosolic protein aggregates by a mechanism that is assisted by autophagy and chaperones. These observations indicate that Schwann cells possess the endogenous ability to clear the misfolded PMP22, however these pathways might become overwhelmed with disease progression and age. The overall aim of this project is to determine if by stimulating the autophagic and chaperone responses of Schwann cells from Trembler J and PMP22 overproducer mice, the abnormal cytosolic aggregation of PMP22 can be suppressed or reversed. We will use well-characterized pharmacologic agents to stimulate these pathways and study the response of the neuropathy Schwann cells in vitro. In parallel, we will test if in vivo modulation of these pathways in neuropathy mice can improve motor performance and resolve the subcellular abnormalities. These studies will determine if modulating the intracellular fate of PMP22 in Schwann cells of neuropathy mice could provide a viable approach for therapy.