UNCOVERING THE RELATIONSHIP BETWEEN HISTONE DEACETYLASES AND BRAIN CHOLESTEROL HOMEOSTASIS

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Astrocyte-specific Transcriptomic Response to PGC-1a Isoforms

Publication . Ribeiro, Mariana Messias de Jesus Rufino; Rodrigues, Elsa; Ruas, Jorge Lira

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 that exert differential and specific biological functions. In the brain, PGC-1α1 has been implicated in reactive oxygen species detoxification but our understanding of the role of the other isoforms is far from complete. Previous results have shown that PGC-1α isoform expression levels can be modulated in the brain by stress conditions, suggesting a functional role for these proteins. Moreover, we have observed that increased expression of PGC-1α3 in astrocytes could be deleterious to neurons. In the adult brain, astrocyte-neuron crosstalk is crucial for neurite outgrowth, dendritic spine maintenance and synaptic function. The main objective of this study was to characterize the molecular pathways controlled by PGC-1α3 in in vitro neuronal and astrocytic experimental models. In parallel, we analysed the transcriptome of astrocytes transduced with a viral vector encoding PGC-1α3 by massively parallel sequencing (RNA-seq) in order to identify its downstream targets. The most striking hits, as well as the expression of other astrocyte-specific genes that could be involved in the neuronal response to PGC-1α3-overexpressing astrocytes, were determined by qPCR. We also used the Ingenuity Pathway Analysis suite to determine which pathways were being modulated as a result of differential expression of the identified hits. Our results show that PGC-1α3 can trigger Gq-coupled protein-mediate calcium dysregulation within astrocytes, inducing secretory pathways and neuroinflammation. In addition, our observations suggest a severe impairment of cell migration. Since proteins secreted by astrocytes play an important role in different neuronal physiological functions, we analyzed our RNA-seq data in order to predict the astrocytic secretome profile. Using a suite of bioinformatic tools we were able to identify candidate proteins putatively secreted through both canonical and non-canonical pathways. Combining these results with the analysis of the differentially expressed genes, led to the identification of Serpini1, Angptl4, galectin 9 and TGFβ as putative PGC-1α3 target genes. Interestingly, an extensive number of transcripts regulated by PGC-1α3 map to pseudogenes, which could potentially include miR sequences. Our results identify for the first-time an astrocyte-specific transcriptomic response to PGC-1α3 expression and highlight PGC-1α isoforms as novel therapeutic targets for the treatment of neurodegenerative diseases.

2018-11-15Dissertação de mestrado

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Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BPD/95855/2013