LRRK2 and RIPK2 Variants in the NOD 2-Mediated Signaling Pathway Are Associated with Susceptibility to Mycobacterium leprae in Indian Populations

Marcinek, Patrick; Jha, Aditya Nath; Shinde, Vidyagouri; Arun, S; Rajkumar, R.; Suryadevara, Naveen Chandra; Neela, Sanjeev Kumar; Tong, Hoang Van; Balachander, Vellingiri; Valluri, Vijaya Lakshmi; Thangaraj, Kumarasamy; Velavan, Thirumalaisamy P.

doi:10.1371/journal.pone.0073103

Cited by 46 publications

(37 citation statements)

References 35 publications

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“…We also found a significantly increased mtDNA copy number in lepromatous leprosy patients11 compared with controls. The mitochondrial outer membrane protein, LRRK2, has been identified by a genome-wide association study (GWAS) as one of the leprosy susceptibility genes in Han Chinese population12, and this was confirmed by our recent case-control study13 and other studies1415, although the associated LRRK2 SNPs or their effects were different in these studies. Most recently, we provided solid evidence to show that the OPA1 gene, encoding an mitochondrial inner membrane protein, was associated with leprosy susceptibility possibly by affecting mitochondrial function and antimicrobial pathways16.…”

supporting

confidence: 53%

Common variants in the PARL and PINK1 genes increase the risk to leprosy in Han Chinese from South China

Wang

Feng

et al. 2016

Sci Rep

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Leprosy is a chronic infectious and neurological disease caused by Mycobacterium leprae, an unculturable pathogen with massive genomic decay and dependence on host metabolism. We hypothesized that mitochondrial genes PARL and PINK1 would confer risk to leprosy. Thirteen tag SNPs of PARL and PINK1 were analyzed in 3620 individuals with or without leprosy from China. We also sequenced the entire exons of PARL, PINK1 and PARK2 in 80 patients with a family history of leprosy by using the next generation sequencing technology (NGS). We found that PARL SNP rs12631031 conferred a risk to leprosy (Padjusted = 0.019) and multibacillary leprosy (MB, Padjusted = 0.020) at the allelic level. rs12631031 and rs7653061 in PARL were associated with leprosy and MB (dominant model, Padjusted < 0.05) at the genotypic level. PINK1 SNP rs4704 was associated with leprosy at the genotypic level (Padjusted = 0.004). We confirmed that common variants in PARL and PINK1 were associated with leprosy in patients underwent NGS. Furthermore, PARL and PINK1 could physically interact with each other and were involved in the highly connected network formed by reported leprosy susceptibility genes. Together, our results showed that PARL and PINK1 genetic variants are associated with leprosy.

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supporting

confidence: 53%

Common variants in the PARL and PINK1 genes increase the risk to leprosy in Han Chinese from South China

Wang

Feng

et al. 2016

Sci Rep

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“…Subsequently, many variants in LRRK2 primary structure have been identified, including dominant mutations segregating with familial PD that also occur in sporadic PD and in cancer 9, together with polymorphisms at the LRRK2 locus that increase the lifetime risk for the development of sporadic PD, but also inflammatory bowel disorder and leprosy 4, 10, 11.…”

Section: Lrrk2 Genetics Protein Domain Structure; Kinase and Gtpase mentioning

confidence: 99%

“…Indeed, activated microglia and monocytes, as well as increased cytokine levels, were reported in PD brains 26. Second, a putative role of LRRK2 in the regulation of the immune response may justify the genetic association of LRRK2 with the susceptibility to inflammatory bowel disorder 10 and leprosy 11 other than with PD.…”

Section: Lrrk2 and The Immune Systemmentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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“…The link to the innate immune response is further reinforced by the genetic association of LRRK2 with susceptibility to inflammatory bowel disorder [11] and leprosy [12, 13]. Moreover, the expression of LRRK2 is modulated by immune cell-specific signals, like IFNγ and toll-like receptor (TLR) agonists [14–16].…”

Section: Introductionmentioning

confidence: 99%

Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons

Maturana¹,

Lang²,

Zubiarrain³

et al. 2016

J Neuroinflammation

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BackgroundMutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both familial and idiopathic forms of Parkinson’s disease (PD). Neuroinflammation is a key event in neurodegeneration and aging, and there is mounting evidence of LRRK2 involvement in inflammatory pathways. In a previous study, we described an alteration of the inflammatory response in dermal fibroblasts from PD patients expressing the G2019S and R1441G mutations in LRRK2.MethodsTaking advantage of cellular reprogramming, we generated induced pluripotent stem cell (iPSC) lines and neurons thereafter, harboring LRRK2G2019S and LRRK2R1441G mutations. We used gene silencing and functional reporter assays to characterize the effect of the mutations. We examined the temporal profile of TNFα-induced changes in proteins of the NF-κB pathway and optimized western blot analysis to capture α-synuclein dynamics. The effects of the mutations and interventions were analyzed by two-way ANOVA tests with respect to corresponding controls.ResultsLRRK2 silencing decreased α-synuclein protein levels in mutated neurons and modified NF-κB transcriptional targets, such as PTGS2 (COX-2) and TNFAIP3 (A20). We next tested whether NF-κB and α-synuclein pathways converged and found that TNFα modulated α-synuclein levels, although we could not detect an effect of LRRK2 mutations, partly because of the individual variability. Nevertheless, we confirmed NF-κB dysregulation in mutated neurons, as shown by a protracted recovery of IκBα and a clear impairment in p65 nuclear translocation in the LRRK2 mutants.ConclusionsAltogether, our results show that LRRK2 mutations affect α-synuclein regulation and impair NF-κB canonical signaling in iPSC-derived neurons. TNFα modulated α-synuclein proteostasis but was not modified by the LRRK2 mutations in this paradigm. These results strengthen the link between LRRK2 and the innate immunity system underscoring the involvement of inflammatory pathways in the neurodegenerative process in PD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0761-x) contains supplementary material, which is available to authorized users.

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LRRK2 and RIPK2 Variants in the NOD 2-Mediated Signaling Pathway Are Associated with Susceptibility to Mycobacterium leprae in Indian Populations

Cited by 46 publications

References 35 publications

Common variants in the PARL and PINK1 genes increase the risk to leprosy in Han Chinese from South China

Common variants in the PARL and PINK1 genes increase the risk to leprosy in Han Chinese from South China

Cellular processes associated with LRRK2 function and dysfunction

Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons

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