Profiling Microglia in a Mouse Model of Machado–Joseph Disease

Biomedicines

Teresa Summavielle¹  António Francisco Ambrósio²  Bruno Fernandes³  Renato Socodato⁴  Camila Cabral Portugal⁴  João Bettencourt Relvas⁴  Ana Bela Campos⁵  Andreia Neves-Carvalho⁵  Patrícia Maciel⁵  Fernanda Marques⁵  Sara Duarte-Silva⁵  Sofia Pereira das Neves⁵  Daniela Monteiro-Fernandes⁵  Andreia Teixeira-Castro⁵ 

[1] Addiction Biology Group, Instituto de Investigação e Inovação em Saúde (i3S), Instituto de Biologia Molecular e Celular (IBMC), University of Porto, 4200-135 Porto, Portugal;Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Univiversity of Coimbra, 3004-504 Coimbra, Portugal;Department of Informatics, ALGORITMI Center, University of Minho, 4710-057 Braga, Portugal;Glial Cell Biology Group, Instituto de Investigação e Inovação em Saúde (i3S), Instituto de Biologia Molecular e Celular (IBMC), University of Porto, 4200-135 Porto, Portugal;Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal;

关键词: microglia;    Machado–Joseph disease;    cell morphology;    RNA-sequencing;    machine learning;   

DOI  :  10.3390/biomedicines10020237

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown