Neurodegenerative diseases represent some of the most devastating neurological disorders, characterized by progressive loss of the structure and function of neurons. Current therapy for neurodegenerative disorders is limited to symptomatic treatment rather than disease modifying interventions, emphasizing the desperate need for improved approaches. Abundant evidence indicates that impaired mitochondrial function plays a crucial role in pathogenesis of many neurodegenerative diseases and so biochemical factors in mitochondria are considered promising targets for pharmacological-based therapies. Peroxisome proliferator-activated receptors-γ (PPARγ) are ligand-inducible transcription factors involved in regulating various genes including peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC1α). This review summarizes the evidence supporting the ability of PPARγ-PGC1α to coordinately up-regulate the expression of genes required for mitochondrial biogenesis in neurons and provide directions for future work to explore the potential benefit of targeting mitochondrial biogenesis in neurodegenerative disorders. We have highlighted key roles of NRF2, uncoupling protein-2 (UCP2), and paraoxonase-2 (PON2) signaling in mediating PGC1α-induced mitochondrial biogenesis. In addition, the status of PPARγ modulators being used in clinical trials for Parkinson’s disease (PD), Alzheimer’s disease (AD) and Huntington’s disease (HD) has been compiled. The overall purpose of this review is to update and critique our understanding of the role of PPARγ-PGC1α-NRF2 in the induction of mitochondrial biogenesis together with suggestions for strategies to target PPARγ-PGC1α-NRF2 signaling in order to combat mitochondrial dysfunction in neurodegenerative disorders.

神经退行性疾病是一些最具破坏性的神经系统疾病，其特征是神经元结构和功能的逐渐丧失。目前对神经退行性疾病的治疗仅限于对症治疗，而不是疾病改变干预措施，这强调了迫切需要改进的方法。大量证据表明，线粒体功能受损在许多神经退行性疾病的发病机制中起着至关重要的作用，因此线粒体中的生化因子被认为是药物治疗的有希望的靶点。过氧化物酶体增殖物激活受体-γ (PPARγ) 是配体诱导转录因子，参与调节多种基因，包括过氧化物酶体增殖物激活受体 γ 共激活物-1 α (PGC1α)。本综述总结了支持 PPARγ-PGC1α 协调上调神经元中线粒体生物发生所需基因表达的能力的证据，并为未来探索靶向线粒体生物发生在神经退行性疾病中的潜在益处的工作提供了方向。我们强调了 NRF2、解偶联蛋白 2 (UCP2) 和对氧磷酶 2 (PON2) 信号在介导 PGC1α 诱导的线粒体生物合成中的关键作用。此外，还编制了用于帕金森病 (PD)、阿尔茨海默病 (AD) 和亨廷顿病 (HD) 临床试验的 PPARγ 调节剂的现状。本综述的总体目的是更新和批评我们对 PPARγ-PGC1α-NRF2 在诱导线粒体生物发生中的作用的理解，并提出针对 PPARγ-PGC1α-NRF2 信号传导以对抗神经退行性疾病中线粒体功能障碍的策略的建议。