Regulation of Autophagy & Mitochondrial Recycling in Neuronal Cell Death

描述（由申请人提供）：维持功能良好的线粒体在神经元健康中起着关键作用。在前一个项目期间，我们发现在几种神经毒素和帕金森病神经变性的遗传模型中神经元损伤集中在通过自噬（线粒体自噬）引起线粒体周转增加。虽然线粒体自噬在某些模型中具有神经保护作用，但在其他模型中，抑制自噬可减少神经突收缩和细胞死亡。我们假设，在这种情况下，通过线粒体生物发生来替换受损/降解的线粒体的能力在确定生存-死亡结果方面是重要的。初步数据表明，细胞外信号调节蛋白激酶2（ERK 2），这表明在帕金森病中脑神经元的线粒体分布改变，在调节线粒体自噬和线粒体生物发生的关键作用。我们将利用分化的神经母细胞瘤细胞，原代胚胎小鼠神经元和体内小鼠模型来研究导致观察到的线粒体含量和功能降低的机制，研究磷酸化在调节生物发生中的作用，并确定调节帕金森病毒素和显性遗传模型中线粒体含量的策略的神经保护潜力。

DESCRIPTION (provided by applicant): The maintenance of well-functioning mitochondria plays a key role in neuronal health. In the previous project period, we found that neuronal injury in several neurotoxin and genetic models of parkinsonian neurodegeneration converged on eliciting increased mitochondrial turnover by autophagy (mitophagy). While mitophagy in some models is neuroprotective, in other models, inhibiting autophagy reduces neurite retraction and cell death. We hypothesize that the capacity to replace damaged/degraded mitochondria through mitochondrial biogenesis is important in determining survival-death outcomes in this context. Preliminary data indicate a key role for extracellular signal-regulated protein kinase 2 (ERK2), which shows an altered mitochondrial distribution in Parkinson's disease midbrain neurons, in regulating both mitophagy and mitochondrial biogenesis. We will utilize differentiated neuroblastoma cells, primary embryonic mouse neurons and in vivo mouse models to study the mechanism(s) leading to the observed decreases in mitochondrial content and function, study the role of phosphorylation in regulating biogenesis, and determine the neuroprotective potential for strategies to modulate mitochondrial content in toxin and dominant genetic models of Parkinson's disease.