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Neurobiol Dis. 2019 May 15;129:67-78. doi: 10.1016/j.nbd.2019.05.012. [Epub ahead of print]

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

Author information

1
Department of Biology, University of Padova, Padova 35131, Italy; Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy. Electronic address: isabella.russo@unibs.it.
2
Department of Biology, University of Padova, Padova 35131, Italy; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: kaganovichal@grc.nia.nih.gov.
3
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: dingj@mail.nih.gov.
4
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: natalie.landeck@nih.gov.
5
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: adamantios.mamais@nih.gov.
6
Department of Biology, University of Padova, Padova 35131, Italy. Electronic address: tatiana.varanita@unipd.it.
7
Department of Biology, University of Padova, Padova 35131, Italy. Electronic address: alice.biosa@unipd.it.
8
Department of Biology, University of Padova, Padova 35131, Italy. Electronic address: isabella.tessari@unipd.it.
9
Department of Biology, University of Padova, Padova 35131, Italy. Electronic address: luigi.bubacco@unipd.it.
10
Department of Biology, University of Padova, Padova 35131, Italy. Electronic address: elisa.greggio@unipd.it.
11
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: cookson@mail.nih.gov.

Abstract

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 α-synuclein pre-formed fibrils (PFFs) or lipopolysaccharide (LPS) as a general inflammatory insult. We observed that, although α-synuclein PFFs and LPS mediate overlapping gene expression profiles in microglia, there are also distinct responses to each stimulus. α-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 α-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.

KEYWORDS:

LRRK2; Microglia; Neuroinflammation; Oxidative stress; Parkinson's disease; α-Synuclein

PMID:
31102768
DOI:
10.1016/j.nbd.2019.05.012

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