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Assaying the Kinase Activity of LRRK2 in vitro
Published on: January 18, 2012
Allele-dependent interaction of LRRK2 and NOD2 in leprosy
Monica Dallmann-Sauer1,2,3,4, Yong Zhong Xu1,2, Ana Lúcia França da Costa5
1Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre; Montreal, Canada.
Abstract:
Leprosy, caused by Mycobacterium leprae, rarely affects children younger than 5 years. Here, we studied a multiplex leprosy family that included monozygotic twins aged 22 months suffering from paucibacillary leprosy. Whole genome sequencing identified three amino acid mutations previously associated with Crohn's disease and Parkinson's disease as candidate variants for early onset leprosy: LRRK2 N551K, R1398H and NOD2 R702W. In genome-edited macrophages, we demonstrated that cells expressing the LRRK2 mutations displayed reduced apoptosis activity following mycobacterial challenge independently of NOD2. However, employing co-immunoprecipitation and confocal microscopy we showed that LRRK2 and NOD2 proteins interacted in RAW cells and monocyte-derived macrophages, and that this interaction was substantially reduced for the NOD2 R702W mutation. Moreover, we observed a joint effect of LRRK2 and NOD2 variants on Bacillus Calmette-Guérin (BCG)-induced respiratory burst, NF-κB activation and cytokine/chemokine secretion with a strong impact for the genotypes found in the twins consistent with a role of the identified mutations in the development of early onset leprosy.
Insights
Genetic mutations in LRRK2 and NOD2 are linked to early-onset leprosy in young children. These variants affect immune cell function and protein interactions, offering insights into rare pediatric leprosy cases.
Area of Science:
- Genetics
- Immunology
- Microbiology
Background:
- Leprosy (Hansen's disease) is caused by Mycobacterium leprae and rarely affects children under five.
- A multiplex family with monozygotic twins presenting with paucibacillary leprosy provided a unique study cohort.
Purpose of the Study:
- To identify genetic variants associated with early-onset leprosy in a pediatric family.
- To investigate the functional impact of identified mutations on immune cell responses to Mycobacterium leprae.
Main Methods:
- Whole genome sequencing to identify candidate mutations.
- Genome-edited macrophages to assess apoptosis and protein interactions (co-immunoprecipitation, confocal microscopy).
- Analysis of immune responses including respiratory burst, NF-κB activation, and cytokine secretion following BCG challenge.
Main Results:
- Three amino acid mutations (LRRK2 N551K, R1398H, and NOD2 R702W) were identified as candidate variants.
- LRRK2 mutations reduced apoptosis in macrophages after mycobacterial challenge, independent of NOD2.
- A significant interaction between LRRK2 and NOD2 proteins was observed, which was diminished by the NOD2 R702W mutation.
- Combined LRRK2 and NOD2 variants showed a joint effect on BCG-induced immune responses, particularly in the twins' genotypes.
Conclusions:
- The identified LRRK2 and NOD2 mutations are associated with early-onset leprosy.
- These variants influence macrophage apoptosis and immune signaling pathways.
- The findings suggest a significant role for these genetic factors in the pathogenesis of pediatric leprosy.
