Differential role of PGC-1α isoforms in the modulation of astrocytes reactive phenotype

• Autor(a) principal: Garcia, Carlota de Sá Lemos
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
• Texto Completo: http://hdl.handle.net/10362/138516
• topic: PGC-1α; astrocytes; cell adhesion; reactive phenotype; inflammation; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a family of transcriptional coactivators that coordinate physiological adaptations in metabolically demanding tissues. In the brain, PGC-1α1, the most well studied PGC-1α isoform, has been implicated in mitochondrial function and reactive oxygen species detoxification. However, our understanding of the remaining isoforms' functions is far from complete. Interestingly, preliminary results from our laboratory showed that in a toxin-based mice model of Parkinson's Disease (PD), the expression levels of PGC-1α2 and PGC-1α3 are increased and that PGC-1α3 overexpression in astrocytes causes detrimental effects on neurons. Herein we aimed to identify the molecular pathways modulated by PGC-1α isoforms by analyzing the transcriptome of astrocytes transduced with adenovirus expressing the different PGC-1α isoforms by massively parallel sequencing, followed by assays to determine the role of these variants in cellular processes identified by this analysis, such as migration, proliferation, adhesion, and inflammatory response. Our results show for the first time that PGC-1α3 ectopic expression significantly decreases mRNA levels of integrins, cadherins and protocadherins, and decreases U118 human glioblastoma and astrocyte cell adhesion. Moreover, PGC-1α3 expression hampers the induction of C-C motif chemokine ligand 2, and lipocalin 2 expression levels in U118 cells treated with a cytokine cocktail used to mimic activation by microglial secretome, and the reactive phenotype of astrocytes when transduced with adenovirus. To identify transcription factors interacting with PGC-1α3 and involved in the regulation of pathways for cell adhesion and immune response, we performed reporter gene assays to identify aryl hydrocarbon receptor (AHR) as a potential transcription factor modulated by PGC-1α3. Preliminary results suggest that PGC-1α3 may modulate the transcriptional activity of AHR, but this effect might be promoter and cell-specific. Collectively, our results highlight PGC-1α isoforms as modulators of astrocytes reactivity and promising therapeutic targets for the treatment of PD and other neurodegenerative disorders.