微管稳定和Rho激酶抑制对α-突触核蛋白致帕金森病轴突损伤的保护作用及机制研究

轴突损伤是帕金森病(PD)早期的特征性改变, α-突触核蛋白(α-syn)异常聚集致神经元损伤早期便可首先出现轴突破坏，因此，促进受损轴突修复或许能早期改善PD进程。但目前α-syn致轴突损伤的机制尚待阐述，也无有效的轴突修复治疗。我们前期发现: 稳定微管或抑制Rho激酶（ROCK）仅能一定程度改善轴突损伤；微管破坏参与了神经元内ROCK的激活，存在某种“微管破坏-ROCK激活”的恶性循环；这提示，针对该恶性循环的“微管稳定”和“ROCK抑制”联合干预具有更好轴突保护的潜能。为此,本申请将以轴突损伤为核心，离体和在体评估“微管稳定”和“ROCK抑制”对受损轴突结构和功能的保护作用；并深入探讨“微管破坏-ROCK激活”这一恶性循环在轴突损伤中的具体作用机制。总之, 本研究有望基于微管和ROCK通路相关靶点从轴突结构和功能修复的角度为PD治疗提供新的思路。

Axon degeneration is likely to be the most striking initial pathological characteristics of Parkinson’s disease (PD). Similarly, in the condition of abnormal α-synuclein (α-syn) aggregation or accumulation, the disease process begins in the distal axon and proceeds retrograde. Therefore, axon may be the most appropriate target for early intervention to forestall the chronic disease progression. However, there are still no detailed mechanisms on the axonal injury, not to mention the clinically available treatment to promote axon regeneration. Previously, we found that microtubule stabilization or Rho kinase (ROCK) inhibition could partially ameliorate the axon injury, which might be explained by the fact that the vicious circle of “microtubule damage - ROCK activation” could not be blocked only by microtubule stabilization or ROCK inhibition. Those results inspire us to perform the combined therapy of “microtubule stabilization” and “ROCK inhibition”. In the current proposal, we will focus on the axon injury, and further explore the effects of “microtubule stabilization” and “ROCK inhibition” in ameliorating the structural and functional injury of axon both in vivo and in vitro. In the mechanism study, we will try to figure out the detailed mechanism of the vicious circle of “microtubule damage- ROCK activation” in axon degeneration. Taken together, our research will help to understand the mechanisms of microtubule depolymerization and ROCK activation in α-syn-mediated axonal injury, offering novel opportunities for the treatment of PD based on the axonal repair and regeneration.