Transcriptome analysis of LRRK2 knock-out microglia cells reveals alterations of inflammatory- and oxidative stress-related pathways upon treatment with α-synuclein fibrils

NEUROBIOLOGY OF DISEASE

卷:129

Article

Russo, Isabella^1,2  Kaganovich, Alice^1,3  Ding, Jinhui³  Landeck, Natalie³  Mamais, Adamantios³  Varanita, Tatiana¹  Biosa, Alice¹  Tessari, Isabella¹  Bubacco, Luigi¹  Greggio, Elisa¹  Cookson, Mark R.³ 

[1] Univ Padua, Dept Biol, I-35131 Padua, Italy

[2] Univ Brescia, Dept Mol & Translat Med, I-25123 Brescia, Italy

[3] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

关键词: LRRK2;    Microglia;    alpha-Synuclein;    Parkinson's disease;    Neuroinflammation;    Oxidative stress;   

DOI  :  10.1016/j.nbd.2019.05.012

来源: Elsevier

【 摘 要 】

Several previous studies have linked the Parkinson's disease (PD) gene LRRK2 to the biology of microglia cells. However, the precise ways in which LRRK2 affects microglial function have not been fully resolved. Here, we used the RNA-Sequencing to obtain transcriptomic profiles of LRRK2 wild-type (WT) and knock-out (KO) microglia cells treated with alpha-synuclein pre-formed fibrils (PFFs) or lipopolysaccharide (LPS) as a general inflammatory insult. We observed that, although alpha-synuclein PFFs and LPS mediate overlapping gene expression profiles in microglia, there are also distinct responses to each stimulus. alpha-Synuclein PFFs trigger alterations of oxidative stress-related pathways with the mitochondrial dismutase Sod2 as a strongly differentially regulated gene. We validated SOD2 at mRNA and protein levels. Furthermore, we found that LRRK2 KO microglia cells reported attenuated induction of mitochondrial SOD2 in response to alpha-synuclein PFFs, indicating a potential contribution of LRRK2 to oxidative stress-related pathways. We validate several genes in vivo using single-cell RNA-Seq from acutely isolated microglia after striatal injection of LPS into the mouse brain. Overall, these results suggest that microglial LRRK2 may contribute to the pathogenesis of PD via altered oxidative stress signaling.

【 授权许可】

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