TARGETING THE MEVALONATE PATHWAY TO TREAT INFLAMMATORY JOINT DISORDERS

Inflammation is the first response of the immune system to invading pathogens or tissue injury.

Environmental factors and/or genetic predispositions can however alter the tight regulation of inflammatory signalling pathways, inducing excessive inflammatory responses which can cause damage to the body.

Mevalonate kinase deficiency (MKD) is an autoinflammatory disease caused by systemic inflammation inducing multi-organ dysfunction.

High levels of the inflammatory cytokine IL-1β is the main cause of the MKD-induced inflammatory phenotype, however the molecular mechanisms responsible for IL-1β production are still unclear.

Previous research has demonstrated that inhibition of prenylation by deficiency in the prenylation enzyme GGTase-I can cause high IL-1β production and the development of joint inflammation as seen in patients with MKD.

More than 100 proteins need to be prenylated for their function and activity, however, the critical unprenylated substrate responsible for inflammatory immune reactions is not known.

Interestingly, treatment with HMGCR inhibitors (such as statins) was shown to mimic effects of GGTase-I deficiency by inducing high IL-1β production in macrophages via hyperactivation of RHO family proteins.

My project aims to identify and validate the critical unlipidated substrate(s) responsible for the development of the inflammatory phenotype in GGTase-I knockout mice, and shed light on the detrimental effects of long-term statin use.