Understanding the Mechanism of Pathological alpha-Synuclein Transmission

α-突触核病症是神经退行性疾病的一个子集，包括帕金森氏病(PD)、 路易体痴呆(DLB)和多系统萎缩(MSA)(1)，特征为 错误折叠的α-突触核蛋白(α-SYN)蛋白在神经元或神经胶质细胞中异常堆积。新出现的证据 提示病理性α-SYN的细胞间传播实质上会导致神经变性。 然而，α-SYN传递的分子机制尚不清楚。我们已经确认了三个 与α-syn PFF强结合的跨膜蛋白：(I)淋巴细胞激活基因-3(LAG3)，(Ii) 淀粉样前体蛋白1(APLP1)和(Iii)神经毒素1-β。LAG3是一种重要的受体，介导 α-SYN PFF的内化；然而，大量的α-SYN PFF与LAG3-/-(基因敲除)神经元结合，提示 一个未知的候选者(S)(例如APLP1)与病理性α-SYN结合，并促进内化。 在这个提议中，我们假设：(I)APLP1是一种重要的受体，介导α-SYN的传递；(Ii) APLP1-LAG3复合体协同介导α-SYN的传播；(Iii)APLP1、LAG3或APLP1- LaG3复合体可减轻α-SYN转基因小鼠α-SYN诱导的神经退行性变。因此， 我们建议用实验来表征APLP1、LAG3和AL复合体在介导细胞死亡过程中的作用。 α-突触核病的细胞间传播模型和α-SYN转基因的发病机制 老鼠模型。在两个α-突触核素病小鼠模型上的实验将得到 细胞和无细胞实验，从而允许破译相互作用中的每个传播步骤 APLP1、LAG3或伴有病理性α-SYN的AL复合体。这些研究的成功完成将 极大地提高了我们对α-SYN细胞间传播的分子机制的理解 受体，通过：(I)确定APLP1是一种新的受体，介导α-SYN的传播，(Ii)了解 AL络合物在介导α-syn PFF结合和内化中的协同作用，(Iii)提供 抗LAG3抗体作为帕金森病及相关疾病潜在治疗剂的初步评价 α-突触核苷酸病，以及(Iv)了解APLP1、LAG3和AL复合体在调节中的作用 α-SYN转基因小鼠的神经变性。

α-Synucleinopathies are a subset of neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy Bodies (DLB) and multiple system atrophy (MSA) (1), which are characterized by abnormal accumulation of misfolded α-synuclein (α-syn) protein in neurons or glial cells. Emerging evidence suggests that the cell-to-cell transmission of pathological α-syn substantially cause neurodegeneration. However, the molecular mechanism of α-syn transmission is poorly understood. We have identified three transmembrane proteins that strongly bind with α-syn PFF: (i) lymphocyte activation gene-3 (LAG3), (ii) amyloid β precursor-like protein 1 (APLP1), and (iii) neurexin 1-β. LAG3 is an essential receptor, mediating internalization of α-syn PFF; however, substantial α-syn PFF binds to LAG3-/- (knockout) neurons, suggesting that a unidentified candidate(s) (e.g. APLP1) binds with pathologic α-syn, and facilitate the internalization. In this proposal, we hypothesize: (i) APLP1 is an essential receptor, that mediates α-syn transmission; (ii) APLP1-LAG3 complex synergistically mediates α-syn transmission; (iii) depletion of APLP1, LAG3, or APLP1- LAG3 complex, can reduce α-syn-induced neurodegeneration of α-syn transgenic mice. Accordingly, experiments are proposed to characterize the roles of APLP1, LAG3 and the AL complex in mediating the pathogenesis of α-synucleinopathies, in cell-to-cell transmission models and the α-syn transgenic mouse model. Experiments in two mice models with α-synucleinopathies, will be complemented by studies in cells and cell-free experiments, thus allowing the deciphering of each spreading step in the interaction of APLP1, LAG3, or the AL complex with pathologic α-syn. The successful completion of these studies will greatly enhance our understanding of the molecular mechanisms of α-syn cell-to-cell transmission via receptors, by: (i) identifying APLP1 as a novel receptor that mediates α-syn spreading, (ii) understanding the synergistic effect of the AL complex on mediating binding and internalization of α-syn PFF, (iii) providing essential preliminary evaluation of anti-LAG3 antibody as a potential therapeutic agent against PD and related α-synucleinopathies, and (iv) understanding the roles of APLP1, LAG3, and the AL complex in mediating neurodegeneration of α-syn transgenic mice.