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

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.

The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration

“…For example, a recent investigation found that mice overexpressing mutant human LRRK2 (either R1441G or G2019S) exhibit increased dopamine neuron loss and neuroinflammation in response to systemic endotoxin challenge. 30 This study concluded that LRRK2 mediated the link between peripheral inflammation and neuroinflammation by augmenting peripheral production of CNS-modulating cytokines. If supported by future research, this finding could also partly explicate the association between PD and Crohn's disease.…”

“…The successful work on microglial TREM2 in AD suggests that it may be important to reconsider the functions of classic PD‐associated genes—such as leucine‐rich repeat kinase 2 ( LRRK2 ), PTEN‐induced kinase 1 ( PINK1 ), and PRKN (Parkin)—and how their mutation or loss could impact microglial biology. For example, a recent investigation found that mice overexpressing mutant human LRRK2 (either R1441G or G2019S) exhibit increased dopamine neuron loss and neuroinflammation in response to systemic endotoxin challenge . This study concluded that LRRK2 mediated the link between peripheral inflammation and neuroinflammation by augmenting peripheral production of CNS‐modulating cytokines.…”

Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia

“…Experimental models also support this connection, whereby IFN-γ has been linked to selective, progressive, DA neurodegeneration in rodents 11,14,15 . More recent studies also point towards the interaction between PDrelated genes and IFN-γ induced DA neuronal loss 16 . The study by Kozina et al shows that human pathogenic mutations in the leucine rich repeat kinase 2 (LRRK2) gene, the most common genetic cause of familial and sporadic PD 17 , synergizes with lipopolysaccharide (LPS)-induced inflammation to potentiate DA neurodegeneration through IFN-γ-mediated immune responses 16 .…”

“…More recent studies also point towards the interaction between PDrelated genes and IFN-γ induced DA neuronal loss 16 . The study by Kozina et al shows that human pathogenic mutations in the leucine rich repeat kinase 2 (LRRK2) gene, the most common genetic cause of familial and sporadic PD 17 , synergizes with lipopolysaccharide (LPS)-induced inflammation to potentiate DA neurodegeneration through IFN-γ-mediated immune responses 16 . Interestingly, LRRK2 is an IFN-γ target gene 18,19 and its expression is increased in immune cells upon IFN-γ stimulation and exposure to pathogens 18,20,21,22,23 .…”

Common neurodegeneration-associated proteins are physiologically expressed by antigen-presenting cells and are interconnected via the inflammation/autophagy-related proteins TRAF6 and SQSTM1

“…Finally, innate immune functions were demonstrated for several genes causatively-linked to familial forms of PD or ALS. These comprise C9ORF72 (21)(22)(23), LRRK2 (Leucine-rich repeat kinase 2) (24)(25)(26)(27), GRN (Granulin Precursor) (28,29) as well as PRKN and PINK1 (30)(31)(32)(33)(34).…”