Numb/Notch信号通路调控一种新的蛋白修饰模式-"寡泛素化"参与Lewy小体形成及其在脑内播散的机制研究

路易小体(LB)是帕金森病(PD)的病理标志，最新研究显示PD致病与LB的形成及在脑内神经元间播散密切相关。LB形成和播散的关键步骤即"α-syn寡聚体"成核聚集；而"α-syn寡泛素化修饰"是α-syn寡聚体形成的启动因素，并调控其细胞间传递的重要环节"胞吞作用"。因此，抑制α-syn寡泛素化修饰，可能有效阻止LB形成及播散。Numb是神经前体细胞分化决定因子，最新研究发现其与Notch相互拮抗，参与凋亡、胞吞作用、泛素蛋白酶体降解等诸多过程。本课题组前期研究证实Numb/Notch信号通路上调α-syn相互作用蛋白Tubulin；而Tubulin可以启动α-syn成核聚集；进一步发现Numb与α-syn存在细胞内共定位及相互结合。本项目将深入探讨Numb/Notch通路调控α-syn寡泛素化参与其包涵体形成及通过胞吞传播的机制，寻找阻断LB形成及播散的干预靶点，为防治PD提供新的方向。

Lewy body (LB) is known as the pathological hallmark of Parkinson' s disease (PD) . Recent studies have suggested that PD attributed to the formation and transmission of LB in the brain. The aggragation of α-synuclein oligomer is the initial step of LB formation; further, Monoubiquitylation of α-synuclein regulate the formation of α-synuclein oligomer and its endocytosis, which is the way of LB dissemination. Therefore, suppression monoubiquitylation of α-synuclein might be an effective way to inhibit the formation and transmission of LB. Numb is the decision factor of neural precursor cell differentiation, antagonism with Notch, takes park in apoptosis, endocytosis, ubiquitin-proteasome degradation physiological process. Our previous studies have confirmed that the Numb/Notch signaling upregulated the level of Tubulin protein, a interactor of a-synuclein and could activate the aggregation of α-synuclein; further, we found colocalization and interaction between Numb and α-synuclein in 293A cells. This study will yield valuable insights into the mechanism of Numb/Notch signaling involved in the formation and transmission of LB through regulates monoubiquitylation of α-synuclein in the brain; and find the new targets for inhibiting the formation and transmission of LB. Try to find a new direction for the prevention and treatment of PD.