Regulation of Autophagy & Mitochondrial Recycling in Neuronal Cell Death

描述（申请人提供）：维持线粒体的良好功能在神经元健康中起着关键作用。在之前的项目期间，我们发现在几种神经毒素和遗传模型的帕金森神经退行性变中，神经元损伤倾向于通过自噬（mitophagy）诱导线粒体更新增加。虽然在某些模型中，自噬具有神经保护作用，但在其他模型中，抑制自噬可减少神经突缩回和细胞死亡。我们假设，在这种情况下，通过线粒体生物发生取代受损/降解线粒体的能力在决定生存-死亡结果中很重要。初步数据表明，细胞外信号调节蛋白激酶2 （ERK2）在调节线粒体自噬和线粒体生物发生中发挥关键作用，这表明帕金森病中脑神经元中线粒体分布的改变。我们将利用分化的神经母细胞瘤细胞、小鼠原代胚胎神经元和小鼠体内模型来研究导致线粒体含量和功能下降的机制，研究磷酸化在调节生物发生中的作用，并确定在帕金森病的毒素和显性遗传模型中调节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.