LRRK2 regulation of immune-pathways and inflammatory disease

Wallings, Rebecca; Tansey, Malú G.

doi:10.1042/bst20180463

Cited by 117 publications

(95 citation statements)

References 116 publications

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“…Specifically, rs7294619 is a significant eVariant that increases only LRRK2 expression in microglia (p = 1.27×10 -6 , beta = 0.263) 26 . The involvement of LRRK2 in microglia dysregulation aligns with substantial previous research implicating this gene in systemic and central nervous system (CNS) inflammation aspects of PD 23,24,30 and other inflammatory diseases 31–33 .…”

Section: Resultssupporting

confidence: 85%

Fine-mapping of Parkinson’s disease susceptibility loci identifies putative causal variants

Schilder

Raj

2020

Preprint

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Recent genome-wide association studies have identified 78 loci associated with Parkinson's Disease susceptibility but the underlying mechanisms remain largely unclear. To identify variants likely causal for disease risk, we fine-mapped these Parkinson's-associated loci using four different statistical and functional fine-mapping methods. We then integrated multi-assay cell-type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus SNPs that disrupt LRRK2 and FCGR2A regulatory elements in microglia, MBNL2 enhancers in oligodendrocytes, and DYRK1A enhancers in neurons. Finally, we confirmed the functional relevance of fine-mapped SNPs using a suite of in silico validation approaches. Together, these results provide a robust list of likely causal variants underlying Parkinson's Disease risk for further mechanistic studies.

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Section: Resultssupporting

confidence: 85%

Fine-mapping of Parkinson’s disease susceptibility loci identifies putative causal variants

Schilder

Raj

2020

Preprint

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“…We identified five distinct clusters of cells based on transcriptome similarity that represent resting microglia and four activation states ( Fig 5F), with PBS-injected animals exhibiting predominantly resting microglia whereas the LPS-injected animals spanned the range of activation states ( Fig 5G). Notably, we did not see strong differences between genotypes other than the KO animals tended to have fewer activated microglia, suggesting that Lrrk2 influences how microglia respond to proinflammatory stimuli (29). Gene ontology showed enrichment for lysosomal and endocytic membrane processes ( Fig 5H).…”

Section: Endolysosomal and Iron-binding Gene Expression In Microglia mentioning

confidence: 81%

Pathogenic mutations in LRRK2 sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

Mamais

Landeck

Langston

et al. 2020

Preprint

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Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson’s disease (PD) while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a are poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a into lysosomes in cells while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive accumulation of endocytosed transferrin into Rab8a-positive lysosomes leading to a dysregulation of iron transport. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in post-mortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.

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“…LRRK2 is a member of the receptor interacting protein (RIP) kinase family, which are a group of proteins that detect and respond to cellular stress by regulating cell death and activation of the immune system (Rideout and Re, 2017), highlighting a potential role of LRRK2 in immune system regulation. This is supported by reports biochemically linking LRRK2 to the pathways regulating inflammation, autophagy and phagocytosis in immune cells (Wallings and Tansey, 2019). Furthermore, polymorphisms in the LRRK2 gene have been linked to inflammatory diseases such as leprosy and the IBD, Crohn's disease (CD), highlighting a critical role of LRRK2 in inflammation.…”

Section: Introductionmentioning

confidence: 77%

“…For example, increased LRRK2 expression in response to microbial pathogens has been observed in human B cells, T cells, macrophages and non-classical monocytes (Gardet et al, 2010;Hakimi et al, 2011;Thévenet et al, 2011;Moehle et al, 2012;Kuss et al, 2014;Cook et al, 2017). Furthermore, LRRK2 is upregulated in unstimulated sporadic-PD neutrophils (Atashrazm et al, 2019), B cells, T cells and non-classical monocytes which is accompanied by increased secretion of pro-inflammatory cytokines from monocytes and T cells (Cook et al, 2017) [reviewed in detail in Lee et al (2017) and Wallings and Tansey (2019)].…”

Section: Lrrk2 Expression In Cells Of the Cns And Peripheral Immune Cmentioning

confidence: 99%

LRRK2 at the Interface Between Peripheral and Central Immune Function in Parkinson’s

2020

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It is becoming increasingly accepted that there is an interplay between the peripheral immune response and neuroinflammation in the pathophysiology of Parkinson's disease (PD). Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene are associated with familial and sporadic cases of PD but are also found in immune-related disorders, such as inflammatory bowel disease (IBD) and leprosy. Furthermore, LRRK2 has been associated with bacterial infections such as Mycobacterium tuberculosis and Salmonella typhimurium. Recent evidence suggests a role of LRRK2 in the regulation of the immune system and modulation of inflammatory responses, at a systemic level, with LRRK2 functionally implicated in both the immune system of the central nervous system (CNS) and the periphery. It has therefore been suggested that peripheral immune signaling may play an important role in the regulation of neurodegeneration in LRRK2 as well as non-LRRK2-associated PD. This review will discuss the current evidence for this hypothesis and will provide compelling rationale for placing LRRK2 at the interface between peripheral immune responses and neuroinflammation.

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LRRK2 regulation of immune-pathways and inflammatory disease

Cited by 117 publications

References 116 publications

Fine-mapping of Parkinson’s disease susceptibility loci identifies putative causal variants

Fine-mapping of Parkinson’s disease susceptibility loci identifies putative causal variants

Pathogenic mutations in LRRK2 sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

LRRK2 at the Interface Between Peripheral and Central Immune Function in Parkinson’s

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