TLR2-interacting domain of MyD88 peptide for alpha-synucleinopathy

有效清除脑实质中聚集的α-SYN有望减缓发展 散发性和家族性帕金森病、路易体痴呆和多系统痴呆的进展 萎缩症(MSA)。研究表明，α-SYN通过TLR2诱导小胶质细胞活化。然而，到目前为止， 目前尚无TLR2的特异性抑制剂。击倒TLR2可能不是一个可行的方法，因为它会抹去 TLR2信号通路包括基础信号通路和诱导信号通路。由于已知TLR2通过MyD88起作用，因此 针对这种诱导的TLR2信号转导，我们从治疗的角度出发，设计了对应于TLR2信号的多肽 MyD88的TLR2相互作用结构域(TIDM)选择性地抑制TLR2信号通路，包括 纤维状α-SYN介导的小胶质细胞激活。因此，在这里，我们想要检验一个新的假设 鼻腔给药wtTIDM多肽抑制神经炎症(特异性目标I)并降低 TLR2介导的A53T转基因小鼠的α-突触核苷酸病(特异性目标II)。这次削减的一个积极结果是- EDGE R21拨款提案将描述是否选择性地瞄准 先天免疫系统(TLR2)由wtTIDM多肽减少路易体病理，突出 发现一种预期的鼻腔给药以减少PD、DLB和MSA的α-突触核病症。 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