Sustained PGC-1a2 or PGC-1a3 expression induces astrocyte dysfunction and degeneration.

Peroxisome proliferator-activated receptor-gamma coactivator-1a (PGC-1a) transcriptional coactivators are key regulators of energy metabolism-related genes and are expressed in energy-demanding tissues. There are several PGC-1a variants with different biological functions in different tissues. The brain is one of the tissues where the role of PGC-1a 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-1a2 and PGC-1a3 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-1a coactivators regulate cellular adaptive responses, we hypothesized that they could be involved in the modulation of astrogliosis induced by MPTP. Therefore, we analysed the transcriptome of astrocytes transduced with expression vectors encoding PGC-1a1 to 1a4 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-1a2 and PGC-1a3, showing that sustained expression of these isoforms induces astrocyte dysfunction and degeneration. This work highlights PGC-1a isoforms as modulators of astrocyte reactivity and potential therapeutic targets for the treatment of PD and other neurodegenerative disorders. Overall design: Comparative gene expression profiling analysis of RNA-seq data from primary mouse astrocytes infected with adenovirus endoding either PGC-1a isoforms or GFP as a control. Experiment contains three replicates for each condition