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-gamma (PPAR gamma) are ligand-inducible transcription factors involved in regulating various genes including peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC1 alpha). This review summarizes the evidence supporting the ability of PPAR gamma-PGC1 alpha 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 PGC1 alpha-induced mitochondrial biogenesis. In addition, the status of PPAR gamma 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 PPAR gamma-PGC1 alpha-NRF2 in the induction of mitochondrial biogenesis together with suggestions for strategies to target PPAR gamma-PGC1 alpha-NRF2 signaling in order to combat mitochondrial dysfunction in neurodegenerative disorders. (C) 2020 Elsevier Inc. All rights reserved.

Automated summary

Neurodegenerative diseases are characterized by the progressive loss of neuron structure and function. Current therapy mainly focuses on symptomatic treatment, but targeting biochemical factors in mitochondria may offer promising treatment options. PPAR gamma-PGC1 alpha plays a crucial role in regulating mitochondrial biogenesis and has been studied in clinical trials for PD, AD, and HD.