PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders

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.