α-synuclein通过抑制施旺细胞NGF分泌及其逆向轴突运输参与多系统萎缩发病机制的研究

α-synuclein在MSA患者周围神经系统的施旺细胞（SC）和感觉神经纤维中异常聚集，但其在MSA发病机制中的作用尚未明确。我们前期研究发现PLP-α-Syn转基因小鼠SC分泌NGF减少，背根神经节（DRG）神经元过表达α-synuclein导致α-tubulin乙酰化水平降低和NGF逆向轴突运输障碍，提示α-synuclein通过影响NGF分泌及其逆向轴突运输参与MSA周围神经损伤。因此，本项目拟深入探讨：1）明确SC中α-synuclein影响内质网-高尔基体-胞外蛋白分泌途径的关键步骤；2）明确DRG神经元中α-synuclein破坏微管乙酰化酶（αTAT1）和去乙酰化酶（HDAC6和SIRT2）之间平衡的具体机制；3）明确NGFR100W联合去乙酰化酶抑制剂ACY-1215和AK7进行治疗是否改善MSA周围神经损伤。课题的开展将帮助完善MSA发病机制研究，为其治疗提供新线索。

α-synuclein deposits in Schwann cells (SC) and sensory neuron fibers in multiple system atrophy (MSA) patients, but its underlying exact mechanisms in the pathogenesis of MSA remain unclear. Our previous study found that, in PLP-α-syn MSA mouse model, the secretion of NGF from SC was reduced, overexpression α-synuclein in DRG sensory neurons reduced the level of acetylated α-tubulin and impaired the retrograde axonal transport of NGF, indicating that the α-synuclein may affect the secretion of NGF from SC and impair the retrograde axonal transport in DRG, and finally contribute the pathogenesis of MSA associated peripheral neuropathy. Base on our previous works, we are going to further investigate: (1) how α-synuclein affect the endoplasmic reticulum-Golgi secretion pathway in SC; (2) how α-synuclein broke the balance between microtubule acetyltransferase (αTAT1) and deacetylases (SIRT2 and HDAC6), and finally lead to the retrograde axonal transport impairment in DRG neurons. (3) whether a combined treatment using NGFR100W with ACY-1215 (a HDAC6 inhibitor) and AK7 (a SIRT2 inhibitor) can improve the MSA associated peripheral neuropathy. This project will help us better understand the role of α-synuclein in MSA pathogenesis and provide a new avenue for treatment of MSA.