Cellular events in heritable peripheral neuropathies

描述（由申请方提供）：遗传性脱髓鞘神经病，包括Charcot-Marie-Tooth病1A型（CMT 1 A），占导致肌肉萎缩和功能障碍的周围神经疾病的很大一部分。外周髓鞘蛋白22（Peripheral myelin protein 22，PMP 22）是一种分子量为22 kD的疏水性膜蛋白，其异常表达与大多数CMT 1A患者相关。在大多数脱髓鞘神经病患者中，PMP 22基因是重复的，而在一小部分CMT 1A和Dejerine-Sottas综合征患者中，PMP 22中存在单个氨基酸取代。对CMT 1A神经活检的研究显示，PMP 22异常保留在雪旺细胞胞质溶胶内，表明蛋白质运输和降解发生了改变。在本资助的当前周期中，我们检测到Trembler J（TrJ）和CMT的PMP 22过表达小鼠模型的Schwann细胞中PMP 22的胞质积累和降解减缓。异常PMP 22的胞质聚集体募集必需的许旺细胞分子，包括分子伴侣、髓鞘蛋白和泛素-蛋白酶体途径的成分，这改变了细胞的蛋白质平衡。在允许的条件下，许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质蛋白质聚集体。这些观察结果表明，许旺细胞具有清除错误折叠的PMP 22的内源性能力，然而这些途径可能随着疾病进展和年龄而变得不堪重负。该项目的总体目标是确定是否通过刺激Trembler J和PMP 22过度生产小鼠的Schwann细胞的自噬和伴侣反应，可以抑制或逆转PMP 22的异常胞质聚集。我们将使用充分表征的药理学试剂来刺激这些通路，并在体外研究神经病雪旺细胞的反应。同时，我们将测试在神经病变小鼠体内调节这些通路是否可以改善运动表现并解决亚细胞异常。这些研究将确定调节神经病小鼠的许旺细胞中PMP 22的细胞内命运是否可以提供可行的治疗方法。

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.