Mechanisms that Kindle Disease in Periodic Hereditary Diseases

Burgh, Robert van der

Prof.dr. A.B.J. (Berent) Prakken
Dr. M.L. (Marianne) Boes
Research group:
Boes , Prakken
May 21, 2015
12:45 h


Autoinflammatory disease is the uncontrolled and recurrent activation of the innate immune response, characterized by the hyper secretion of interleukin-1β by monocytes. Most known autoinflammatory diseases have a genetic origin. In the autoinflammatory disease mevalonate kinase deficiency there is a mutation in the enzyme mevalonate kinase, reducing its activity to below 10% of the wild type enzyme. This deficiency leads to reduced prenylation (lipid modification) of proteins and results in disease.

In this thesis we investigate the molecular mechanisms of how reduced prenylation leads to IL-1β secretion. We determined that reduced prenylation leads to the accumulation of damaged mitochondria. Failure in clearance causes mitochondrial content to leak into the cytosol and activate the immune response. Furthermore we found that the activity and localization of small GTPases Rac1 and RhoA is altered. Lack of prenylation increases Rac1 activity and decreases RhoA activity. We also studied a mutant version of SerpinB9, an endogenous inhibitor of the IL-1β converting enzyme caspase-1, and its contribution to the development of autoinflammatory disease. The findings in this thesis shed light on the molecular basis of autoinflammatory disease and can be used to identify future targets for therapeutic intervention. 

Full text