Is LRRK2 the missing link between inflammatory bowel disease and Parkinson’s disease?

Herrick, Mary K.; Tansey, Malú G.

doi:10.1038/s41531-021-00170-1

Cited by 64 publications

(47 citation statements)

References 105 publications

(134 reference statements)

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“…The M2397T variant affects LRRK2 protein levels and is associated with IBD ( 45 ). The variant N2081D has shared effects with increased risks of PD and CD, whereas R1398H and N551K were related to reduced risks of PD and CD ( 46 , 47 ). The two susceptibility loci (FCGR2A and NOD2) identified in the largest GWAS meta-analysis of PD are also closely related to IBD pathogenesis ( 9 , 31 ).…”

Section: Discussionmentioning

confidence: 98%

Are neurodegenerative diseases associated with an increased risk of inflammatory bowel disease? A two-sample Mendelian randomization study

Cui

et al. 2022

Front. Immunol.

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BackgroundSeveral studies have shown that neurodegenerative diseases (e.g., Parkinson’s disease [PD] and Alzheimer’s disease [AD]) are associated with inflammatory bowel disease (IBD), but the causality and direction of their associations remain unclear. Mendelian randomization (MR) studies have explored the causal effects of IBD on PD and AD. However, only a few studies examined this reverse association. Thus, this study aimed to explore whether there are causal associations of genetically predicted PD and AD with IBD, using a two-sample MR study.MethodsSummary statistics for IBD, ulcerative colitis (UC), and Crohn’s disease (CD) were derived from a genome-wide association study (GWAS) meta-analysis, which included the International IBD Genetics Consortium and the UK IBD Genetics Consortium (n=59,957). Genetic variants associated with the largest meta-analysis of GWAS of PD (n=1,474,097) and AD (n=455,258) were used as instrumental variables. We used multiple methods, including inverse variance weighted (IVW), weighted median (WM), MR-Egger regression, weighted mode, and Robust Adjusted Profile Score (RAPS) methods, to estimate the effects of genetically predicted PD and AD on IBD. To confirm the validity of the analysis, we also evaluated the pleiotropic effects, heterogeneity, and leave-one-out sensitivity analysis that drive causal associations.ResultsThe results of the IVW method, WM, and RAPS showed that genetically predicted PD was significantly associated with an increased risk of UC (odds ratio [OR]IVW=1.068, ORWM=1.107, ORRAPS=1.069, all P<0.05). Additionally, we found that there were significant associations of genetically predicted PD with CD (ORIVW=1.064, ORRAPS=1.065, all P<0.05) and IBD (ORIVW=1.062, ORRAPS=1.063, all P<0.05) using the IVW method and RAPS. However, there was no significant causal evidence of genetically predicted AD in IBD, UC, or CD among all MR methods. In all MR analyses, there were no horizontal pleiotropy (all P>0.05), or statistical heterogeneity. The sensitivity analysis results of the leave-one-out sensitivity analysis showed that the causal effect estimations of genetically predicted PD and AD on IBD were robust.ConclusionsOur MR study corroborated a causal association between genetically predicted PD and IBD but did not support a causal effect of genetically predicted AD on IBD. More animal experiments or population-based observational studies are required to clarify the underlying mechanisms of PD and IBD.

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Section: Discussionmentioning

confidence: 98%

Are neurodegenerative diseases associated with an increased risk of inflammatory bowel disease? A two-sample Mendelian randomization study

Cui

et al. 2022

Front. Immunol.

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“…In targeting pathways important for mounting immunological responses to different types of challenges, there could be adverse consequences with blocking LRRK2 in innate immune cells. Some of these issues have been discussed by others recently and in depth [ 44 , 62 ]. Future studies utilizing chemokine-receptor antagonists and other therapeutic candidates in the context of over-active mutant LRRK2 and α-synuclein fibril-induced neurodegeneration may be informative.…”

Section: Discussionmentioning

confidence: 99%

Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain

Boddu

Abdelmotilib

et al. 2022

Mol Neurodegeneration

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Background Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson’s disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers. Brain-engrafting pro-inflammatory monocytes have been implicated in dopaminergic neurodegeneration in PD models. Here we examine how α-synuclein and LRRK2 interact in monocytes and subsequent neuroinflammatory responses. Methods Human and mouse monocytes were differentiated to distinct transcriptional states resembling macrophages, dendritic cells, or microglia, and exposed to well-characterized human or mouse α-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to α-synuclein fibrils in R1441C-Lrrk2 knock-in mice or G2019S-Lrrk2 BAC mice were evaluated by flow cytometry. Chemotaxis assays were performed with monocyte-derived macrophages stimulated with α-synuclein fibrils and microglia in Boyden chambers. Results α-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, α-synuclein fibrils stimulate LRRK2 through JAK-STAT activation and intrinsic LRRK2 kinase activity in a feed-forward pathway that upregulates phosphorylated Rab10. In contrast, LRRK2 expression and Rab10 phosphorylation are both suppressed in microglia-like cells that are otherwise highly responsive to α-synuclein fibrils. Corroborating these results, LRRK2 expression in the brain parenchyma occurs in pro-inflammatory monocytes infiltrating from the periphery, distinct from brain-resident microglia. Mice expressing pathogenic LRRK2 mutations G2019S or R1441C have increased numbers of infiltrating pro-inflammatory monocytes in acute response to α-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens α-synuclein fibril and microglia-stimulated chemotaxis. Conclusions Pathologic α-synuclein activates LRRK2 expression and kinase activity in monocytes and induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain.

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“…LRRK2 mutations are the most prevalent causes of familial PD [ 71 , 72 , 73 ]. LRRK2 mutations are also related to various disorders such as Crohn’s disease, ulcerative colitis, leprosy, and cancer [ 74 , 75 , 76 , 77 , 78 , 79 ]. To date, over 80 mutations in LRRK2 have been reported; however, the role of 8 mutations in PD was significantly highlighted in many reports [ 80 ].…”

Section: Lrrk2 Mutationsmentioning

confidence: 99%

“…There are multiple additional variations associated with PD risk, including A419V, N551K, R1325Q, R1398H, T1410M, R1628P, M1646T, S1647T, N2081D etc. [ 74 , 77 , 86 , 87 , 88 , 89 ]. It is currently unknown to what extent these risk mutations influence the kinase activity of LRRK2 and require further investigations.…”

Section: Lrrk2 Mutationsmentioning

confidence: 99%

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD. Consequently, the identification of potential LRRK2 inhibitors has been the focus of drug discovery. Various investigations have been conducted in academic and industrial organizations to investigate the mechanism of LRRK2 in PD and further develop its inhibitors. This review summarizes the role of LRRK2 in PD and its structural details, especially the kinase domain. Furthermore, we reviewed in vitro and in vivo findings of selected inhibitors reported to date against wild-type and mutant versions of the LRRK2 kinase domain as well as the current trends researchers are employing in the development of LRRK2 inhibitors.

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Is LRRK2 the missing link between inflammatory bowel disease and Parkinson’s disease?

Cited by 64 publications

References 105 publications

Are neurodegenerative diseases associated with an increased risk of inflammatory bowel disease? A two-sample Mendelian randomization study

Are neurodegenerative diseases associated with an increased risk of inflammatory bowel disease? A two-sample Mendelian randomization study

Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

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