Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.

许多研究表明线粒体功能障碍是帕金森病 (PD) 细胞损失的关键因素。先前对路易体病变患者多巴胺能（DAergic）神经元的分析揭示了线粒体呼吸的核编码基因缺陷，其中许多是转录因子雌激素相关受体γ（Esrrg）的靶标/ERRγ）。我们证明，从成年小鼠的 DAergic 神经元中删除 ERRγ 足以导致线粒体基因表达和数量减少的左旋多巴反应性 PD 样表型，ERRγ 的部分缺乏会加速突触核蛋白介导的毒性，并且 ERRγ 过表达减少了包涵体负载和延迟突触核蛋白介导的细胞丢失。虽然 ERRγ 缺失并没有完全概括在死后组织中观察到的转录改变，但它导致涉及突触和线粒体功能以及自噬的基因减少。总而言之，这些实验表明 ERRγ 缺陷小鼠可以提供一个模型来理解 DAergic 神经元中的转录调控和扩增 ERRγ -介导的转录程序应被视为促进 PD 中 DAergic 维持的策略。