帕金森病（PD）患者出现运动缺陷和频繁的抑郁和焦虑。线粒体缺陷和炎性小体激活与PD发病机制有关，但他们在PD病理学原因中的关系未知。PINK1-/-小鼠（PD模型）表现出线粒体和成体海马神经发生（AHN）缺陷，应激诱导的抑郁行为增加，神经胶质介导的神经炎症增加。因此，该小鼠提供一个好的模型来阐明PD病理学原因中线粒体缺陷和神经炎症之间的相互关系。我们提出PINK1缺失会加剧线粒体缺陷，导致炎性小体的持续过度激活，这与抑郁症和运动缺陷有因果关系。我们将测量慢性心理压力下小鼠体内线粒体功能，炎症小体激活状态，下丘脑 - 垂体 - 肾上腺（HPA）轴活动，AHN和抑郁行为等指标，并尝试用针对线粒体损伤和炎症小体的抑制剂来逆转这些病理学改变。此外我们将使用PD相关的线粒体应激物来探讨PINK1是否可以预防炎性小体介导的多巴胺功能障碍和运动缺陷。该研究有助于开发减缓PD病情发展的新疗法。

Parkinson’s disease (PD) affects ~ 2% of the population ages 60 and above, which amounts to more than 2.5 million patients in China. PD is marked by severe movement deficits and frequent psychological disturbances in the form of depression, anxiety and cognitive deterioration. We have established the PINK1-deficient (PINK1-/-) mouse model of familial PD that captures several pathophysiological mechanisms and phenotypes relevant to PD. Specifically, loss of the mitochondrial kinase PINK1 induces characteristic mitochondrial dysfunction and increased glia-mediated neuroinflammation, associated with reduced levels of dopamine, impairments of adult hippocampal neurogenesis (AHN) and increased susceptibility to stress-induced depressive behaviors. Hence, the PINK1-/- model is ideally suitable to elucidate how the diverse disease-causing pathways coordinate and interact with each other to produce PD. Here, we hypothesize that PINK deficiency exacerbates stress-induced mitochondrial deficits, leading to persistent and aberrant activation of the inflammasome in brain areas, which consequently disrupts the integrity of the motor pathways (substantia nigra, striatum) as well as psycho-affective circuits (hippocampus, medial prefrontal cortex). It will be investigated under three specific aims:.1..We will characterize how mitochondrial deficits specific to PINK1 deletion activate the inflammasome and de-regulate the hypothalamus-pituitary-adrenal (HPA) stress axis in response to chronic stress..2..We will use specific inhibitors (drugs) of mitochondrial damage/stress and the inflammasome to dissect the mutual link between mitochondrial deficits and neuroinflammation in the emergence of stress-induced AHN deficits and depression, and to attempt reversal of these pathologies in PINK1-/- mice..3..We will test whether PINK1 protects against inflammasome-mediated dopaminergic deficits and motor impairments by exposing mice to the mitochondrial complex I inhibitor/toxin MPTP (sporadic PD model) and chronic psychological stress...The proposed experiments will generate new insights into the mechanisms and sequential events that cause movement disorder and depression in PD. This new knowledge can be readily translated into novel disease-modifying therapies for PD, and at the same time should also benefit the treatment of depressive symptoms in other neurodegenerative diseases and major depression.