TLR2-interacting domain of MyD88 peptide for alpha-synucleinopathy

从脑实质中有效清除聚集的α-syn有望减少脑梗死的发生。 散发性和家族性PD、路易体痴呆（DLB）和多系统 萎缩（MSA）。已显示α-syn通过TLR 2诱导小胶质细胞活化。然而，直到现在， 没有特异性的TLR 2抑制剂。TLR 2的敲除可能不是一种可行的方法，因为它会消除 基础和诱导的TLR 2信号通路。由于已知TLR 2通过Myd 88起作用， 为了从治疗角度靶向这种诱导的TLR 2信号传导，我们设计了一种对应于 选择性抑制TLR 2信号通路的MyD 88的TLR 2相互作用结构域（TIDM），包括 纤维状α-syn介导的小胶质细胞活化。因此，在这里，我们想测试一个新的假设， 鼻内施用wtTIDM肽抑制神经炎症（具体目的I）并降低 通过TLR 2在A53 T转基因小鼠中的α-突触核蛋白病（特定目的II）。这次裁员的一个积极结果是- 边缘R21授权提案将描述是否选择性地以 先天性免疫系统（TLR 2）的wtTIDM肽减少路易体病理，突出了 发现了一种减少PD、DLB和MSA中α-突触核蛋白病的前瞻性鼻内药物。 1

Effective clearance of aggregated α-syn from the brain parenchyma is expected to reduce the development and progression of both sporadic and familial PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). It has been shown that α-syn induces microglial activation via TLR2. However, until now, there is no specific inhibitor of TLR2. Knockdown of TLR2 may not be a feasible approach as it would wipe out both basal as well as induced TLR2 signaling pathways. Since TLR2 is known to function via Myd88, to target this induced TLR2 signaling from the therapeutic angle, we have designed a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that selectively inhibits TLR2 signaling pathway including fibrillar α-syn-mediated microglial activation. Therefore, here, we want to test a novel hypothesis that intranasal administration of wtTIDM peptide suppresses neuroinflammation (Specific aim I) and decreases α-synucleinopathy (Specific aim II) in A53T transgenic mice via TLR2. A positive outcome of this cutting- edge R21 grant proposal will delineate if selective targeting of activated status of one component of the innate immune system (TLR2) by wtTIDM peptide reduces Lewy body pathology, highlighting the discovery of a prospective intranasal agent to reduce α-synucleinopathy in PD, DLB and MSA. 1