PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders
Open accessAbstract
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.
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PGC1α signaling is a master regulator of mitochondrial biogenesis and energy metabolism with significant therapeutic relevance in neurodegenerative diseases, including ALS.
“The PGC1α signaling is a master regulator of mitochondrial biogenesis and energy metabolism with significant therapeutic relevance in neurodegenerative diseases, including ALS.349”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [349]
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References 244 · Cited by 236
Research works printed but not linked: 2
- Da Cruz S, Parone PA, Lopes VS, Lillo C, McAlonis-Downes M, Lee SK, … Williams DS (2012b). Elevated PGC1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS. Cell Metabolism 15, 778– 786. 22560226 PMC3565468
- de Oliveira Bristot VJ, de Bem Alves AC, Cardoso LR, da Luz Scheffer D, & Aguiar AS Jr. (2019). The role of PGC1α/UCP2 signaling in the beneficial effects of physical exercise on the brain. Frontiers in Neuroscience 13, 292. 30983964 PMC6449457
- Authors
- Jamwal, S., Blackburn, J. K., & Elsworth, J. D.
- Affiliations
- Yale University (US)
- Corresponding author
- Elsworth, John D.
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 219
- Pages
- 107705
- ISSN
- 0163-7258 (ISSN-L)
- PMC
- PMC7887032
- OpenAlex
- W3092161393
- Cited by
- 236
- References
- 244
- Citations by year
- 2026: 43 · 2025: 74 · 2024: 50 · 2023: 29 · 2022: 22 · 2021: 17 · 2020: 1
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- PPARγ, PGC-1α, mitochondrial biogenesis, neurodegenerative diseases, Nrf2, UCP2, paraoxonase 2, mitochondrial dysfunction, Parkinson's disease, Alzheimer's disease, Huntington's disease, PPARγ modulators, therapeutic target
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Organelle Biogenesis, Humans, Neurodegenerative Diseases, Aryldialkylphosphatase, PPAR gamma, NF-E2-Related Factor 2
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