LRRK2 regulates innate immune responses and neuroinflammation during <i>Mycobacterium tuberculosis</i> infection

Weindel, Chi G; Bell, Samantha L.; Huntington, Taylor E.; Vail, Krystal J.; Srinivasan, Rahul; Patrick, Kristin L.; Watson, Robert O.

doi:10.1101/699066

Cited by 5 publications

(4 citation statements)

References 81 publications

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“…A newly identified LRRK2-N2081D mutation, which is located in the kinase domain, is potentially associated with increased risk for both PD and CD [ 10 ]. Additionally, LRRK2 mutations were reported to aggravate the type-1 reaction in leprosy, and the innate immune response against Mycobacterium tuberculosis [ 11 , 12 ]. These findings indicate a potentially important role of LRRK2 at the interface between the peripheral and the central nervous system (CNS) immunity.…”

Section: Introductionmentioning

confidence: 99%

Tissue specific LRRK2 interactomes reveal a distinct striatal functional unit

et al. 2023

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Mutations in LRRK2 are the most common genetic cause of Parkinson’s disease. Despite substantial research efforts, the physiological and pathological role of this multidomain protein remains poorly defined. In this study, we used a systematic approach to construct the general protein-protein interactome around LRRK2, which was then evaluated taking into consideration the differential expression patterns and the co-expression behaviours of the LRRK2 interactors in 15 different healthy tissue types. The LRRK2 interactors exhibited distinct expression features in the brain as compared to the peripheral tissues analysed. Moreover, a high degree of similarity was found for the LRRK2 interactors in putamen, caudate and nucleus accumbens, thus defining a potential LRRK2 functional cluster within the striatum. The general LRRK2 interactome paired with the expression profiles of its members constitutes a powerful tool to generate tissue-specific LRRK2 interactomes. We exemplified the generation of the tissue-specific LRRK2 interactomes and explored the functions highlighted by the “core LRRK2 interactors” in the striatum in comparison with the cerebellum. Finally, we illustrated how the LRRK2 general interactome reported in this manuscript paired with the expression profiles can be used to trace the relationship between LRRK2 and specific interactors of interest, here focusing on the LRRK2 interactors belonging to the Rab protein family.

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Section: Introductionmentioning

confidence: 99%

Tissue specific LRRK2 interactomes reveal a distinct striatal functional unit

et al. 2023

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“…We conclude, from our results, that LRRK2 is an inhibitor of host inflammation (2). This conclusion is supported by the interesting observation, also quoted by Zhang et al (1), that Mycobacterium tuberculosis (Mtb) induced neuroinflammation in Lrrk2 KO mice (10). Similarly, a Lrrk2 knockout had been shown to enhance the proinflammatory cytokine response to Mtb (11).…”

mentioning

confidence: 59%

Reply to Zhang et al.: The differential role of LRRK2 variants in nested leprosy phenotypes

Fava

Cobat

Gzara

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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We thank Dr. Zhang et al. (1) for their thought-provoking comments and addition of exciting results to our recent study that identifies an overlap in the genetic control of type-1 reaction (T1R) and Parkinson's disease (PD) (2). To put the comments by Zhang et al. into context, the purpose and design of our study is to analyze the contribution of rare variants to T1R by contrasting T1R-affected with T1R-free leprosy patients. Our study is not designed to test for common variants or the impact of genetic variants on leprosy per se susceptibility. Rather, our study deals with the role of specific genetic variants in the development of T1R among leprosy patients, and we never state or imply that the PRKN and LRRK2 genes have an exclusive impact on T1R but not leprosy. Indeed, we have published extensively on the role of common PRKN variants in leprosy susceptibility (3,4) As for PRKN, the two markers listed by Zhang et al.(1) do not show evidence for significant association with T1R in our study (2). We find that the V380L marker, which is not significant on its own, contributes to the rare variant analysis but not to an extent that impacts the overall conclusion about the contribution of rare PRKN variants to T1R risk. Given the nonsignificant effect of V380L, we do not attempt to do any functional validation of this particular variant.Stimulated by the data of Zhang et al.(1) for LRRK2, we compared the R1628P distribution between T1R-affected and T1R-free leprosy cases of our sample against 472 ethnically matched healthy controls. For T1R-free

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“…LRRK2 is predominantly expressed in immune cells (macrophages and monocytes) of the CNS, certain peripheral tissues, and blood, which led to the hypothesis that LRRK2 has its main function in innate immunity [ 92 , 93 , 94 ]. In this context, it is also important to note that single nucleotide polymorphisms (SNPs) in LRRK2 have been associated with higher susceptibility to bacterial infections and chronic inflammatory diseases such as Crohn’s disease and leprosy [ 95 , 96 , 97 , 98 ]. Unlike other alterations in LRRK2, the most common mutation, G2019S, is not completely penetrant, meaning that not all individuals harboring the single nucleotide change will develop PD [ 99 ].…”

Section: Disease Modeling: Animal Models Patient-derived Ipsc Models and Cell-based 3d Models And Platformsmentioning

confidence: 99%

The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease

Badanjak

Fixemer

Smajić

et al. 2021

IJMS

169

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With the world’s population ageing, the incidence of Parkinson’s disease (PD) is on the rise. In recent years, inflammatory processes have emerged as prominent contributors to the pathology of PD. There is great evidence that microglia have a significant neuroprotective role, and that impaired and over activated microglial phenotypes are present in brains of PD patients. Thereby, PD progression is potentially driven by a vicious cycle between dying neurons and microglia through the instigation of oxidative stress, mitophagy and autophagy dysfunctions, a-synuclein accumulation, and pro-inflammatory cytokine release. Hence, investigating the involvement of microglia is of great importance for future research and treatment of PD. The purpose of this review is to highlight recent findings concerning the microglia-neuronal interplay in PD with a focus on human postmortem immunohistochemistry and single-cell studies, their relation to animal and iPSC-derived models, newly emerging technologies, and the resulting potential of new anti-inflammatory therapies for PD.

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LRRK2 regulates innate immune responses and neuroinflammation during Mycobacterium tuberculosis infection

Cited by 5 publications

References 81 publications

Tissue specific LRRK2 interactomes reveal a distinct striatal functional unit

Tissue specific LRRK2 interactomes reveal a distinct striatal functional unit

Reply to Zhang et al.: The differential role of LRRK2 variants in nested leprosy phenotypes

The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease

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