Sustained PGC-12 or PGC-13 expression induces astrocyte dysfunction and degeneration

Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) transcriptional coactivators are key regulators of energy metabolism-related genes and are expressed in energy-demanding tissues. There are several PGC-1 alpha variants with different biological functions in different tissues. The brain is one of the tissues where the role of PGC-1 alpha 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-1 alpha 2 and PGC-1 alpha 3 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-1 alpha coactivators regulate cellular adaptive responses, we hypothesized that they could be involved in the modulation of astrogliosis induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP). Therefore, we analysed the transcriptome of astrocytes transduced with expression vectors encoding PGC-1 alpha 1 to 1 alpha 4 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-1 alpha 2 and PGC-1 alpha 3, showing that sustained expression of these isoforms induces astrocyte dysfunction and degeneration. This work highlights PGC-1 alpha isoforms as modulators of astrocyte reactivity and as potential therapeutic targets for the treatment of PD and other neurodegenerative disorders.