Sustained PGC-1α2 or PGC-1α3 expression induces astrocyte dysfunction and degeneration

Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) transcriptional coactivators are key regulators of energy metabolism-related genes and are expressed in energy-demanding tissues. There are several PGC-1α variants with different biological functions in different tissues. The brain is one of the tissues where the role of PGC-1α isoforms remains less explored. Here, we used a toxin-based mouse model of Parkinson's disease (PD) and observed that the expression levels of variants PGC-1α2 and PGC-1α3 in the nigrostriatal pathway increases at the onset of dopaminergic cell degeneration. This increase occurs concomitant with an increase in glial fibrillary acidic protein levels. Since PGC-1α coactivators regulate cellular adaptive responses, we hypothesized that they could be involved in the modulation of astrogliosis induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, we analysed the transcriptome of astrocytes transduced with expression vectors encoding PGC-1α1 to 1α4 by massively parallel sequencing (RNA-seq) and identified the main cellular pathways controlled by these isoforms. Interestingly, in reactive astrocytes the inflammatory and antioxidant responses, adhesion, migration, and viability were altered by PGC-1α2 and PGC-1α3, showing that sustained expression of these isoforms induces astrocyte dysfunction and degeneration. This work highlights PGC-1α isoforms as modulators of astrocyte reactivity and as potential therapeutic targets for the treatment of PD and other neurodegenerative disorders.

Descrição

Funding Information: This work is funded by FEDER through the Lisbon Regional Operational Program Lisbon 2020 and by National Funds through Foundation for Science and Technology under the LISBOA-01-0145-FEDER-030104 ; PTDC/MEDFSL/030104/2017 project, and by the Swedish Research Council. Publisher Copyright: © 2023 The Authors

Palavras-chave

Adhesion Astrocyte reactivity Isoforms Migration Parkinson's disease PGC-1α PGC-1α2 PGC-1α3 Variants Viability Pathology and Forensic Medicine Histology Cell Biology

URI

http://hdl.handle.net/10362/167643

DOI

10.1016/j.ejcb.2023.151377

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