间断θ节律刺激通过自噬对抗帕金森病的机制研究

The repeated transcranial magnetic stimulation (rTMS) is widely used in neurological/neuropsychiatric disease treatment, for its painless, noninvasive and high efficiency. However, the efficacy of iTBS is influenced by multiple parameters, and the underlying mechanism remains unclear, resulting in limitations of its clinical application on Parkinson's disease (PD) treatments. Our previous study found that a new rTMS technology, intermittent theta burst stimulation (iTBS) significantly improved the motor coordination and protected the dopaminergic neurons in MPTP/p PD mice. And iTBS also enhanced autophagy to reduce the accumulation of α-synulein in MPTP/p PD mice. In the present study, we intend to evaluate the effects of iTBS against PD both in MPTP/p PD mice and in AAV1/2-A53T α-syn PD rats. We propose autophay involves in the protection of iTBS against PD by downregulating the accumulation of α-synulein in the brain. The results not only reveal a new mechanism underlying the neuroprotections of iTBS, but also provide a theoretical basis for the further development of iTBS in the clinical application.

重复经颅磁刺激（repeated transcranial magnetic stimulation, rTMS）因无创高效简便等多重优势被广泛应用于神经精神疾病的治疗。但由于参数较多，机制不明等问题，严重限制了其在帕金森病（Parkinson’s disease，PD）的应用。我们前期研究发现，rTMS新技术间断θ节律刺激（intermittent theta burst stimulation，iTBS）显著改善MPTP/p小鼠的运动障碍保护多巴胺能神经元。同时，iTBS增强MPTP/p小鼠中脑自噬减少α-synculein聚集。本项目拟制备MPTP/p小鼠和AAV1/2-A53T α-synuclein大鼠PD模型系统评价iTBS对抗PD病变的作用，研究其通过自噬降低脑内α-synculein蓄积的机制。研究结果将揭示iTBS神经保护的新机制，为iTBS临床应用的拓展提供理论基础。

重复经颅磁刺激(repetitive transcranial magnetic stimulation,rTMS)作为一项无创无痛、安全有效且简便易操作的诊疗技术，在临床具有广阔的应用前景。间歇性θ爆发式刺激(intermittent theta burst stimulation,iTBS)是rTMS最新开发的应用模式，目前主要用于精神疾病的实验性治疗，帕金森病症(Parkinson’s disease,PD)等神经系统疾病方面涉及很少且机制不明，严重限制了iTBS在临床的应用。本项目前期研究发现，iTBS可改善MPTP/p小鼠的运动障碍减轻中脑多巴胺能神经元损伤；与此同时还发现，MPTP/p小鼠细胞自噬水平提高，中脑内α-syn的异常聚集随之下降。本项目进一步应用6-OHDA诱导的PD大鼠模型研究长期给予iTBS对抗PD病变的疗效及其作用机制。结果与MPTP/p小鼠一致，iTBS主要通过抑制脑内兴奋性毒性，调节自噬水平降低α-syn蓄积从而改善PD所致行为学障碍和病理学损伤。溶酶体膜上的阳离子转运体ATP13A2敲除可取消iTBS对MPTP/p模型小鼠运动协调能力障碍的改善，同时取消iTBS对MPTP/p模型小鼠纹状体和黑质区多巴胺能神经元的保护作用，揭示iTBS的神经保护作用确实依赖于ATP13A2介导的自噬溶酶体途径。此外，我们对iTBS神经保护机制的研究还发现，miR-551b-TRIM31介导的泛素蛋白酶体途径可能也参与其中。综上所述，本项目工作的研究结果为iTBS抗PD病变提供了直接的支持证据，并阐明其在PD神经损伤中发挥多靶点的保护作用机制，为iTBS临床应用的拓展提供了理论基础，为临床防治PD提供了新的思路和策略。