Campos Ana Bela, Duarte-Silva Sara, Fernandes Bruno, das Neves Sofia Pereira, Marques Fernanda, Teixeira-Castro Andreia, Neves-Carvalho Andreia, Monteiro-Fernandes Daniela, Portugal Camila Cabral, Socodato Renato, Summavielle Teresa, Ambrósio António Francisco, Relvas João Bettencourt, Maciel Patrícia
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal.
ICVS/3B's, PT Government Associate Laboratory, 4710-057 Braga, Portugal.
Biomedicines. 2022 Jan 23;10(2):237. 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.
小胶质细胞在神经退行性疾病（NDs）中的作用日益受到关注，并且已经为其中几种NDs定义了特定的疾病相关小胶质细胞（DAM）特征。然而，Machado-Joseph病（MJD）中的小胶质细胞特征仍未得到探索。在此，我们对MJD的CMVMJD135小鼠模型中的小胶质细胞特征进行了表征。这种表征分别使用从新生和成年CMVMJD135小鼠的疾病相关脑区获得的原代小胶质细胞培养物和小胶质细胞进行。实施机器学习模型以根据小胶质细胞的形态特征识别潜在的小胶质细胞簇，并进行RNA测序分析以识别分子扰动和潜在的治疗靶点。我们的研究结果揭示了形态学改变，表明CMVMJD135小鼠中小胶质细胞的激活状态增加，以及MJD小胶质细胞的疾病特异性转录谱，总共包括101个差异表达基因，在与氧化应激、免疫反应、细胞增殖、细胞死亡和脂质代谢相关的分子途径中富集。总体而言，这些结果使我们能够定义与MJD相关的小胶质细胞的细胞和分子特征，并识别可能代表该疾病潜在治疗靶点的基因和途径。
