Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease

Abstract

Type-1 reactions (T1R) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the genewise enrichment of rare protein-altering variants in 7 genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy patients of which 237 were T1R-affected and 237 were T1R-free matched controls. Genewise enrichment of nonsynonymous variants was tested with both kernel-based (sequence kernel association test [SKAT]) and burden methods. Of the 7 genes tested 2 showed statistical evidence of association with T1R. For the LRRK2 gene an enrichment of nonsynonymous variants was observed in T1R-free controls (PSKAT-O = 1.6 × 10−4). This genewise association was driven almost entirely by the gain-of-function variant R1628P (P = 0.004; odds ratio = 0.29). The second genewise association was found for the Parkin coding gene PRKN (formerly PARK2) where 7 rare variants were enriched in T1R-affected cases (PSKAT-O = 7.4 × 10−5). Mutations in both PRKN and LRRK2 are known causes of Parkinson’s disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that amino acids in Parkin targeted by nonsynonymous T1R-risk mutations were also enriched for mutations implicated in PD (P = 1.5 × 10−4). Hence, neuroinflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping genetic control of pathogenicity.

Crystal structure of human PACRG in complex with MEIG1

“…Parkin and PINK1 have recently been implicated in mitochondria-dependent inflammation, in response to bacterial infection or mitochondrial stress [8][9][10]. Intriguingly, SNPs and missense variants in LRRK2, a gene associated with autosomal dominant PD, have also been linked to susceptibility, inflammatory responses and type-1 reactions in leprosy [12,45,46]. LRRK2 is a large protein of the ROC-COR family of protein kinases, which regulates intracellular trafficking via phosphorylation of Rab GTPases, which are key mediators of pathways implicated in PD [47].…”

“…We extended our analysis to MEIG1, PACRGL, and other axonemal proteins (SPAG16, FAP20, and FAP206), as well as PINK1 and DJ-1, two proteins implicated in PD and which regulate mitochondrial homeostasis [38]. Furthermore, we also included LRRK2, a kinase associated with both leprosy and PD [12]. We found a strong correlation (r = 0.88) between the expression of Parkin and PINK1, with both expressing at very high levels in mitochondria-rich tissues such as muscles and the central nervous system ( Figure 6).…”

“…While Parkin or PINK1 knockout (KO) mice do not exhibit significant muscle or neuronal degeneration on their own [6,7], mitochondrialinked stress and infection-induced inflammation can induce neurodegeneration in those strains [8][9][10]. Parkin KO mice are more susceptible to intracellular bacterial pathogens [11], and missense mutations in Parkin are associated with an increased susceptibility to a type-1 reaction in leprosy, a disease caused by a chronic Mycobacterium leprae infection [12]. Furthermore, a previous study showed that susceptibility to leprosy was strongly associated with genetic variants in the promoter region of Parkin [13].…”

Leucine Rich Repeat Kinase 2 and Innate Immunity

“…The largest association with T1R susceptibility was the rs3761863 SNP previously identified for CD, that encodes the LRRK2 M2397T variant (Fava et al, 2016). However, in a replication study, the same authors demonstrate that the main association between LRRK2 and T1R susceptibility, is actually provided by a protective variant (R1628P) enriched in T1R-free subjects (Fava et al, 2019). Thus, as for PD and IBD, the genetics underlying LRRK2 susceptibility to Leprosy or subsequent complications, likely involves a complex interplay of both risk and protective alleles.…”

“…Intriguingly, mice with the G2019S LRRK2 mutation showed improved bacterial control of S. typhimurium (Shutinoski et al, 2019), adding to suggestions that some LRRK2 mutations may constitute an evolutionary advantage against infection (Herbst and Gutierrez, 2019). Indeed, LRRK2 kinase activity has also been associated with improved clearance of M. tuberculosis (Hartlova et al, 2018) and protective alleles identified that improve clearance of M. leprae (Fava et al, 2019). However, context again appears to be important with LRRK2 knockout mice showing increased susceptibility to L. monocytogenes (Zhang et al, 2015).…”