The Role of Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha in Type 2 Diabetes Mellitus and Neurodegenerative Diseases: A Systematic Review of Preclinical Evidence

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), encoded by PPARGC1A, plays an important role in the regulation of mitochondrial biogenesis, metabolism, and energy balance. Alterations in PGC-1α function have been found in type 2 diabetes mellitus (T2DM) and neurodegenerative diseases (NDs), but molecular similarities in these pathologies have not been comprehensively studied yet. The current systematic review provides a synthesis of preclinical data on the role of PGC-1α in relation to T2DM and NDs. This study was performed in accordance with the PRISMA 2020 statement. PubMed, Scopus, Web of Science and ScienceDirect were screened for studies published between January 2015 and March 2025. Preclinical studies, including in vivo animal studies with and without in vitro studies, were evaluated for risk of bias according to the SYRCLE checklist and modified CAMARADES checklist. Due to the high heterogeneity, data were qualitatively synthesized. Eleven preclinical studies met the inclusion criteria. Decreased PGC-1α signalling was indicated to be linked to mitochondrial dysfunction, oxidative stress, glucose metabolism impairment, insulin resistance and neurodegeneration via AMPK, SIRT1, CREB, FOXO, PPARγ, Parkin/PARIS, and BDNF pathways. Pharmacological interventions and exercise support increased PGC-1α signalling, potentially improved mitochondrial functions and metabolism and facilitated neuronal survival. Though most studies had a low risk of bias, methodological limitations were quite prevalent. PGC-1α is a key molecular mediator between metabolic dysfunction and neurodegeneration and is a potential target for intervention. However, more rigorous translational and clinical studies are required for the validation of results. This systematic review has not been prospectively registered.