Bridging Pleiotropic Mechanisms in Leprosy Type-1 Reactions and Neurodegenerative diseases

  1. Vinicius M. Fava
  2. Jônatas Perico
  3. Marianna Orlova
  4. Monica Dallmann-Sauer
  5. Yong Zhong Xu
  6. Nguyen Van Thuc
  7. Vu Hong Thai
  8. Andrea F. Belone
  9. Ana Carla P Latini
  10. Erwin Schurr
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Abstract

Leprosy is an infectious disease that affects predominantly the skin and peripheral nervous system. Sudden episodes of hyperinflammation, known as Type 1 Reactions (T1R), are a main contributor to permanent nerve damage in leprosy. The genetic component associated with the neuro-inflammatory phenotype of T1R displays pleiotropic effects with Parkinson’s disease (PD) risk genes. In this study, we further explored the genetic overlap between PD and T1R and expanded the evaluation of pleiotropic effects between T1R and other neurodegenerative disorders. We first replicated the association of PD-risk rare variants inPRKNwith T1R in Vietnamese leprosy patients (P= 0.04; OR = 3.1). Additionally, we discovered largePRKNstructural variants only in T1R-affected participants when compared to T1R-free leprosy patients. Analysis of 24 PD associated genes revealed compound effects between rare protein-altering variants and T1R in the interacting genesPRKN/PINK1(P= 2.7−05; OR = 4.0) and a combination of rare/low frequency variants in theLRRK2/GAKpair (P= 6.7−05; OR = 0.54). These findings validated a genetic overlap between T1R and PD with two distinct axes, one of shared risk viaPRKN/PINK1and a second of antagonistic pleiotropic effects viaLRRK2/GAK. When testing an additional 94 genes associated with neurodegenerative diseases other than PD, we identified variants in the amyotrophic lateral sclerosis (ALS) disease-risk geneTBK1associated with T1R (P= 0.004; OR = 12.9). AllTBK1mutations in T1R-affected participants located to the ubiquitin-like TBK1 domain.PRKN,PINK1andTBK1play a critical role in autophagy and in the host immune response toMycobacteria. Our results highlight shared biological processes between leprosy and neurodegenerative diseases, which may indicate candidate drugs for repurposing for a more favorable T1R management.

AUTHORS SUMMARY

In this study, we investigated the shared genetic component between hyperinflammatory processes in leprosy and neurodegenerative diseases. A subset of leprosy patients develop sudden episodes of severe inflammation, known as type-1 reactions (T1R), which frequently lead to permanent nerve injury. Here, we aimed to identify key genetic mediators of nerve damage shared with diseases of the central nervous system and T1R, which affects the peripheral nervous system. Previous studies showed Parkinson’s disease (PD) risk genes associated with T1R. To explore this further, we analyzed 24 well-established PD-risk genes in over 800 Vietnamese leprosy patients. We found that rare mutations inPRKNandPINK1were more frequent in individuals experiencing T1R. These genes are involved in mitochondrial quality control and responses to intracellular pathogens. Inversely, theLRRK2andGAKPD-risk genes were associated with protection from T1R. This pattern suggested two independent biological processes influencing T1R susceptibility. Our findings highlight a shared genetic component between PD and T1R and suggest that therapies developed for PD may be repurposed for T1R management. Our results underscore the value of cross-disease research to uncover new therapeutic strategies, particularly for neglected diseases with limited treatments or therapies with frequent adverse effects.

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