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Brain. 2018 Jun 1;141(6):1753-1769. doi: 10.1093/brain/awy077.

Mutant LRRK2 mediates peripheral and central immune responses leading to neurodegeneration in vivo.

Author information

1
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Blvd, Memphis TN 38105, USA.
2
Department of Neurosciences, Jefferson Hospital for Neuroscience, Thomas Jefferson University, 900 Walnut St, Philadelphia PA 19107, USA.
3
Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Blvd, Memphis TN 38105, USA.
4
Department of Hematology, St. Jude Children's Research Hospital, 262 Danny Thomas Blvd, Memphis TN 38105, USA.
5
St. Jude Proteomics Facility, St. Jude Children's Research Hospital, 262 Danny Thomas Blvd, Memphis TN 38105, USA.
6
Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Blvd, Memphis TN 38105, USA.

Abstract

Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene result in late-onset Parkinson's disease. The incomplete penetrance of LRRK2 mutations in humans and LRRK2 murine models of Parkinson's disease suggests that the disease may result from a complex interplay of genetic predispositions and persistent exogenous insults. Since neuroinflammation is commonly associated with the pathogenesis of Parkinson's disease, we examine a potential role of mutant LRRK2 in regulation of the immune response and inflammatory signalling in vivo. Here, we show that mice overexpressing human pathogenic LRRK2 mutations, but not wild-type mice or mice overexpressing human wild-type LRRK2 exhibit long-term lipopolysaccharide-induced nigral neuronal loss. This neurodegeneration is accompanied by an exacerbated neuroinflammation in the brain. The increased immune response in the brain of mutant mice subsequently has an effect on neurons by inducing intraneuronal LRRK2 upregulation. However, the enhanced neuroinflammation is unlikely to be triggered by dysfunctional microglia or infiltrated T cells and/or monocytes, but by peripheral circulating inflammatory molecules. Analysis of cytokine kinetics and inflammatory pathways in the peripheral immune cells demonstrates that LRRK2 mutation alters type II interferon immune response, suggesting that this increased neuroinflammatory response may arise outside the central nervous system. Overall, this study suggests that peripheral immune signalling plays an unexpected-but important-role in the regulation of neurodegeneration in LRRK2-associated Parkinson's disease, and provides new targets for interfering with the onset and progression of the disease.

Comment in

PMID:
29800472
DOI:
10.1093/brain/awy077
[Indexed for MEDLINE]

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