Neural circuits underlying motor impairments in a rodent model of progressive supranuclear palsy

项目摘要/摘要 PTEN诱导的蛋白激酶1(PINK1)基因突变导致常染色体隐性遗传性帕金森病(PD)。 帕金森病的主要病理特征是黑质致密部多巴胺神经元的丢失， 它们是正常运动和形成被称为路易小体的富含α-突触核蛋白聚集体所必需的 包裹体。来自我们实验室的初步数据和发表的关于PINK1基因敲除(KO)大鼠的报告表明 大鼠存在线粒体功能障碍，运动功能障碍，黑质和定位神经元丢失 蓝斑和α-突触核蛋白聚集在不同的脑区域，包括黑质、纹状体和 大脑皮层。PINK1是一种线粒体靶向激酶，参与清除受损的线粒体。在神经元中， 线粒体主要位于突触前末端，在那里它们提供所需的能量 囊泡运动和突触传递。α-突触核蛋白也主要定位于突触前 据报道，在突触终末，突触小泡从储备池移动到容易的 可释放池。鉴于线粒体和α-突触核蛋白对突触传递的重要性，以及 PINK1缺乏对线粒体健康和α-突触核蛋白积聚的影响尚待确定 PINK1KO大鼠是否存在突触传递缺陷。目前也不清楚α-突触核蛋白的病理 仅仅是受损线粒体积累的最终副产品，或者，它是否直接导致 观察PINK1KO大鼠的病理过程。我们的初步发现，以及发表的报告， 导致我们假设PINK1缺乏会导致α-突触核蛋白聚集，从而导致级联反应 突触功能障碍，运动异常，和多巴胺能神经元丢失。确定α-突触核蛋白的作用 在PINK1KO大鼠的病理生理学方面，我们将利用电生理学、组织学和 生化和行为分析。结果将表明α-突触核蛋白聚集本身是否推动了 观察到的病理学，回答了靶向α-突触核蛋白干预以停止或减缓的重要性 帕金森病进展。

Project Summary/Abstract Mutations in the PTEN induced kinase 1 (PINK1) gene cause autosomal recessive Parkinson's disease (PD). The main pathological hallmarks of PD are loss of dopamine neurons in the substantia nigra pars compacta, which are required for normal movement, and the formation of α-synuclein rich aggregates termed Lewy body inclusions. Preliminary data from our lab and published reports on PINK1 knockout (KO) rats have demonstrated that the rats have mitochondrial dysfunction, locomotor deficits, loss of neurons in the substantia nigra and locus coeruleus, and α-synuclein aggregates in different brain regions including the substantia nigra, striatum, and cortex. PINK1 is a mitochondrial targeted kinase involved in the clearance of damaged mitochondria. In neurons, mitochondria are predominantly located in the pre-synaptic terminal, where they provide the energy needed for vesicle movement and synaptic transmission. α- Synuclein is also predominantly localized to the pre-synaptic terminal where it has reported functions in movement of synaptic vesicles from the reserve pool to the readily releasable pool. Given the importance of both mitochondria and α-synuclein to synaptic transmission, and the effect of PINK1 deficiency on mitochondrial health and α-synuclein accumulation, it remains to be determined whether PINK1 KO rats have deficits in synaptic transmission. It is also unknown whether α-synuclein pathology is simply an end byproduct of the accumulation of damaged mitochondria or, whether it directly contributes to the observed pathological processes in PINK1 KO rats. Our preliminary findings, as well as published reports, have led us to the hypothesis that PINK1 deficiency leads to α-synuclein aggregation, which causes a cascade of synaptic dysfunction, locomotor abnormalities, and dopaminergic neuron loss. To determine α-synuclein's role in the pathophysiology of PINK1 KO rats, we will utilize a combination of electrophysiological, histological, biochemical and behavioral analyses. The results will indicate whether α-synuclein aggregation itself drives the observed pathology, providing an answer to the importance of targeting α-synuclein interventions to halt or slow PD progression.