Pharmacological Modulation of Parkin Expression and Function to Attenuate Mitochondrial Dysfunction

我们的目标是确定增加神经元细胞中蛋白质parkin数量的药物样分子。帕金在一些帕金森病（PD）患者中发生突变。帕金去除受损的线粒体（细胞的动力），保护神经元免受细胞死亡。在开发出增加parkin水平的新分子后，我们的目标是确定它们在PD模型中的治疗潜力，并表征药物如何增加parkin水平。 编码PINK1和Parkin的基因突变导致早发性家族性PD。与果蝇中的遗传研究一致，表明PINK1在相同途径中在帕金上游起作用，生物化学和细胞生物学研究表明，PINK1将帕金招募到受损的线粒体中，帕金可以诱导受损线粒体的选择性自噬。PINK1是一种激酶，已显示磷酸化Parkin以触发Parkin与线粒体的缔合。Parkin是一种E3泛素连接酶，可泛素化线粒体上的大量底物。这些泛素化的底物将诸如p62的衔接子募集到线粒体，这些衔接子被认为是启动受损线粒体的自噬体识别的关键。帕金活动通过线粒体自噬或替代途径保护神经元免受各种压力。 体外和体内研究表明，增加帕金表达改善线粒体质量控制，并保护多巴胺能神经元免受与衰老相关的线粒体应激。由于衰老被认为是散发性PD的主要风险因素，因此功能失调的线粒体的积累是治疗干预的有吸引力的途径。我们寻求发现和验证提高Parkin表达水平和泛素连接酶活性的药物，以逆转PD中的线粒体功能障碍和神经元丢失。

Our aim is to identify drug-like molecules that increase the amount of the protein parkin in neuronal cells. Parkin is mutated in some people with Parkinsons disease (PD). Parkin removes damaged mitochondria (the powerhouses of the cells), which protects neurons from cell death. After developing new molecules that increase levels of parkin, our goal is to determine their therapeutic potential in PD models and to characterize how the drugs increase parkin levels. Mutations in genes encoding PINK1 and Parkin cause early onset familial PD. Consistent with genetic studies in Drosophila that indicate PINK1 functions upstream of Parkin in the same pathway, biochemical and cell biology studies show that PINK1 recruits Parkin to damaged mitochondria where Parkin can induce selective autophagy of damaged mitochondria . PINK1 is a kinase that has been shown to phosphorylate Parkin to trigger Parkin association with mitochondria. Parkin is an E3 ubiquitin ligase that ubiquitinates scores of substrates on mitochondria. These ubiquitinated substrates recruit adaptors such as p62 to mitochondria that are thought to be key for initiating autophagosome recognition of damaged mitochondria. Parkin activity through mitophagy or alternative pathways protects neurons from a variety of stresses. In vitro and in vivo studies indicate that increasing Parkin expression improves mitochondria quality control and protects dopaminergic neurons from mitochondrial stressors associated with aging. As aging is regarded as the primary risk factor for sporadic PD, it is logical the accumulation of dysfunctional mitochondria is an attractive avenue for therapeutic intervention. We seek to discover and validate drugs that boost Parkin expression level and ubiquitin ligase activity to reverse mitochondrial dysfunction and neuron loss in PD.