Mevalonate Kinase is a key enzyme in the cholesterol biosynthetic pathway and is responsible for converting mevalonic acid to mevalonate-5-phosphate, an early intermediate in sterol and isoprenoid synthesis. Mutations in the
MVK gene (12q24) encoding Mevalonate Kinase enzyme (MVK) cause Mevalonate Kinase Deficiency (MKD, OMIM #260920) and its more severe form, Mevalonic Aciduria (MA, OMIM #610377). The latter is characterized by recurrent attacks of fever, developmental delay, ataxia, dysmorphic features, failure to thrive, cataracts, and retinal dystrophy. The prognosis is poor: few patients survive until adolescence and more than 50% of them succumb to an inflammatory crisis during the first years of life [
1]. One of the characteristics of this disease is cerebellar atrophy, due to neuronal apoptosis [
2].
Although the genetic defects are well known and characterized, the pathogenic mechanism remains elusive, and treatment of the disease remains mainly supportive, with poor efficacy. For an evidence-based therapy, it is crucial to determine the exact pathogenic mechanisms occurring in the disease. Animals or cell-based models are thus necessary; in the past a mouse model of MVK deficiency was generated [
3] however it was unable to correctly represent the pathology. Then a cellular model have been developed, where the mevalonate pathway is pharmacologically targeted using HMG-CoA blockers (statins), mimicking some of the inflammatory features observed in cells from patients [
4]. Using this strategy, our group and other authors have found that, in different cell lines, NALP3 inflammasome activation is responsible for initiating inflammation [
4-
6]. This multi-molecular complex, constituted by NALP3, ASC and Caspase-1, cleaves pro-IL-1β to release its active form, starting inflammation [
7]. Accordingly, NALP3 activation could represent a possible starting point for MA pathogenic progression. A number of issues need to be clarified, such as how the inflammasome pathway is incorrectly activated in cells presenting the pathological mutations. In the attempt to better mimic MA pathology we developed a novel murine cell model in which
MVK expression is specifically down-regulated, using the silencing RNA (siRNA) technology. We then compared the results obtained by siRNA transfection with those achieved with Lovastatin and LPS treatment, in order to determine the better model suitable for mimicking the pathologic condition.