Proposed mechanism for LRRK2 in T1R.
The LRRK2 M2397T amino acid substitution affects protein turnover. The methionine variant of LRRK2 displays a half-life of approximately 8 hours while the half-life of the threonine variant is 18 hours . LRRK2 arrests the NFAT transcription factor in the cytoplasm through a complex mechanism mediated by Ca2+ . This prevents NFAT to migrate to the nucleus and trigger the expression of pro-inflammatory cytokines . The M2397 allele is in tight linkage disequilibrium with alleles of SNPs that promote an increase in LRRK2 expression creating a compensatory mechanism to counterbalance the shorter LRRK2-M2397 half-life. This compensatory mechanism is abrogated in the presence of M. leprae antigen. Hence, the effect of the M2397T amino acid substitution is most pronounced in the presence of M. leprae antigen.