Profiling microglia in a mouse model of Machado–Joseph disease

• Published in: Biomedicines Vol. 10(2); no. 2; pp. 1 - 27
• Main Authors: Campos, Ana Bela, Silva, Sara Duarte, Fernandes, Bruno, Neves, Sofia Pereira das, Marques, Fernanda, Castro, Andreia Teixeira, Carvalho, Andreia Neves, Fernandes, Daniela Monteiro, Portugal, Camila Cabral, Socodato, Renato, Summavielle, Teresa, Ambrósio, António Francisco, Relvas, João Bettencourt, Maciel, Patrícia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 23-01-2022; MDPI AG
• Subjects: Animal models; Antibodies; Cell cycle; Cell death; Cell morphology; Cell proliferation; Disease; DNA damage; Gene expression; Homeostasis; Immune response; Laboratory animals; Learning algorithms; Lipid metabolism; Machado–Joseph disease; Machine learning; Microglia; Microglia Machado–Joseph disease; Microglial cells; Morphology; Neonates; Neurodegenerative diseases; Oxidative stress; Pathogenesis; Pathogens; RNA-sequencing; Senescence; Sequence analysis; Therapeutic applications; Therapeutic targets; Transcription; St Louis Missouri; United States > US; RNA-sequencing; cell morphology; machine learning; microglia; Machado–Joseph disease
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines10020237

Microglia have been increasingly implicated in neurodegenerative diseases (NDs), and specific disease associated microglia (DAM) profiles have been defined for several of these NDs. Yet, the microglial profile in Machado–Joseph disease (MJD) remains unexplored. Here, we characterized the profile of microglia in the CMVMJD135 mouse model of MJD. This characterization was performed using primary microglial cultures and microglial cells obtained from disease-relevant brain regions of neonatal and adult CMVMJD135 mice, respectively. Machine learning models were implemented to identify potential clusters of microglia based on their morphological features, and an RNA-sequencing analysis was performed to identify molecular perturbations and potential therapeutic targets. Our findings reveal morphological alterations that point to an increased activation state of microglia in CMVMJD135 mice and a disease-specific transcriptional profile of MJD microglia, encompassing a total of 101 differentially expressed genes, with enrichment in molecular pathways related to oxidative stress, immune response, cell proliferation, cell death, and lipid metabolism. Overall, these results allowed us to define the cellular and molecular profile of MJD-associated microglia and to identify genes and pathways that might represent potential therapeutic targets for this disorder.