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.