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

M. J. Nunes, A. N. Carvalho, C. Sá-Lemos, M. Colaço, I. Cervenka, V. Ciraci, S. G. Santos, M. M. Ribeiro, M. Castanheira, P. R. Jannig, M. J. Gama, M. Castro-Caldas, C. M. P. Rodrigues, E. Rodrigues, J. L. Ruas

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Abstract

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.
Original languageEnglish
Article number151377
Number of pages20
JournalEuropean Journal Of Cell Biology
Volume103
Issue number1
DOIs
Publication statusPublished - Mar 2024

Keywords

  • Adhesion
  • Astrocyte reactivity
  • Isoforms
  • Migration
  • Parkinson's disease
  • PGC-1α
  • PGC-1α2
  • PGC-1α3
  • Variants
  • Viability

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