Abstract
Leucine rich repeat kinase 2 (LRRK2) was recently identified in genome-wide
association studies (GWAS) as a major susceptibility gene for Crohn’s disease.
We found that LRRK2 deficiency confers enhanced susceptibility to
experimental colitis in mice. Mechanistic studies showed that LRRK2 is a potent
negative regulator of the transcription factor NFAT and a component of the
complex involving a non-coding RNA repressor of NFAT (NRON).
Correspondingly, the risk-associated allele Met2397 identified in CD GWAS
causes a post-translational reduction in LRRK2 protein. We found that severe
colitis in LRRK2-deficient mice is associated with enhanced NFAT1 nuclear
localization. Thus, our study defines a new step in the control of NFAT activation
that involves an immunoregulatory function of LRRK2 and has important
implications for inflammatory bowel disease.
