STN DBS-Mediated BDNF Signaling and Neuroprotection in the Context of PFF-Seeded Synucleinopathy

项目摘要/摘要 帕金森氏病(PD)是仅次于阿尔茨海默氏症的第二大神经退行性疾病 这是一种严重的疾病，是社会的主要负担。帕金森病是一种进行性疾病，会导致各种症状 包括痴呆症、自主神经和运动功能障碍；所有这些都会导致患者的生活质量下降 个人。目前的治疗方法有助于恢复运动功能，但没有改变疾病的方法 阻止或延缓帕金森病进展的治疗方法。丘脑底核的深部脑刺激(DBS) (STN)治疗帕金森病的主要运动症状的频率越来越高。STN DBS通常会 被用作最后的治疗手段，只有在患者对药物治疗不再有反应后才考虑。 因此，接受STN DBS治疗的患者平均在确诊后12-14年。验尸研究 检查早期帕金森病受试者发现，绝大多数壳核去神经已经 发生在确诊后的头3-5年内。因此，STN DBS能否提供 对于黑质纹状体变性的神经保护，除了症状缓解外，还有待于 适当的早期临床队列。事实上，最近的一项临床试点研究表明，STN DBS在 早期帕金森病患者安全有效，也提示了疾病的改善作用。临床前 我们小组和其他人的研究表明，STN DBS在使用神经毒剂之前或之后使用 去甲肾上腺素(MPTP，6-OHDA)对大鼠黑质纹状体多巴胺(DA)神经元变性的保护作用 以及非人灵长类动物。在我们的实验室中，我们已经直接将STN DBS的神经保护潜力 刺激诱导的脑源性神经营养因子-原肌球蛋白受体B型激动子 黑质致密部(SNPC)神经元的信号传导。与神经毒物模型的结果相反， STN DBS在α-SYN过表达模型中的应用在神经保护方面产生了好坏参半的结果。 因此，STN DBS能否在共核病的背景下保护黑质纹状体系统仍是一个 这是个未解决的问题。在目前的提案中，我将使用一种替代的联核症模型，该模型已经很好地- 本实验室以大鼠为研究对象，研究STN-DBS介导的神经保护问题。这 模型是通过注射预先形成的α-SYN纤维(PFF)诱导的，并提供了检测 内源性α-SYN水平正常的联核症。超生理学α-SYN表达不是 与帕金森病的α-SYN水平相似，可能导致与帕金森病发病机制无关的神经毒性机制。AS 这样，α-SYN PFF模型可能比α-SYN过表达模型与疾病更相关。在《目标1》中，我将 检测STN DBS对PFF诱导的磷酸化α-SYN(PSyn)包涵体和BDNF-TrkB的影响 SNPC中pSyn积累高峰时的信号转导。在目标2中，我将调查是否启动STN 黑质pSyn蓄积后的DBS具有神经保护作用。总的来说，这些研究将提供 支持或反驳STN DBS对抗突触核病的神经保护潜力的证据。

Project Summary/Abstract Parkinson’s disease (PD) is the second most common neurodegenerative disorder behind Alzheimer’s disease, and is a major burden to society. PD is a progressive disorder resulting in a variety of symptoms including dementia, autonomic, and motor dysfunction; all contributing to a diminished quality of life for afflicted individuals. Current treatments help to restore motor function, however there are no disease-modifying treatments that halt or slow the progression of PD. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is applied with increasing frequency to treat the cardinal motor symptoms of PD. STN DBS has typically been used as a treatment of last resort, considered only after patients no longer respond to pharmacotherapy. As a result, the average patient undergoing STN DBS is 12-14 years post diagnosis. Post mortem studies examining early PD subjects reveal that the overwhelming majority of putaminal denervation has already occurred within the first 3-5 years after diagnosis. Therefore, the question of whether STN DBS can provide neuroprotection against nigrostriatal degeneration, beyond symptomatic relief, remains to be examined in the appropriate early stage clinical cohort. Indeed, a recent clinical pilot study has demonstrated that STN DBS in early stage PD patients is safe and efficacious, and also suggests a disease modifying effect. Preclinical studies by our group and others have demonstrated that STN DBS applied prior to, or following neurotoxicant insult (MPTP, 6-OHDA) can protect against degeneration of nigrostriatal dopamine (DA) neurons in both rats and nonhuman primates. In our laboratory we have directly linked the neuroprotective potential of STN DBS with stimulation-induced brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase type B (trkB) signaling in substantia nigra pars compacta (SNpc) neurons. In contrast to results in neurotoxicant models, STN DBS applied in α-syn overexpression models has yielded mixed results with regards to neuroprotection. Whether STN DBS can protect the nigrostriatal system in the context of synucleinopathy therefore remains an open question. In the present proposal I will use an alternative synucleinopathy model that has been well- characterized by our laboratory in rats to examine the question of STN DBS-mediated neuroprotection. This model is induced by injection of pre-formed α-syn fibrils (PFF) and offers the ability to examine synucleinopathy in the context of normal endogenous α-syn levels. Supraphysiological α-syn expression is not analogous to α-syn levels in PD and may result in neurotoxic mechanisms unrelated to PD pathogenesis. As such, the α-syn PFF model may be more disease-relevant than α-syn overexpression models. In Aim 1, I will examine the impact of STN DBS on PFF-induced phosphorylated α-syn (pSyn) inclusions and BDNF-TrkB signaling during the peak of pSyn accumulation in the SNpc. In Aim 2 I will investigate whether initiating STN DBS following nigral pSyn accumulation provides neuroprotection. Collectively, these studies will provide evidence to support or refute the neuroprotective potential of STN DBS against synucleinopathy.