Molecular mechanisms responsible for neuroinflammation and neurological impairments in mevalonate kinase deficiency

Abstract

Mevalonate kinase deficiency (MKD) is due to by pathogenic mutations in the MVK gene that cause a reduced activity of the enzyme [1]. Specifically, it is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent fevers. Although the knowledge of MKD pathogenesis has increased, the link between genetic defect and phenotype, especially as regard to the severe neurologic impairments, is not yet clear. To date the most accredited pathogenic hypothesis is that the typical neurodegeneration is linked both to the intrinsic apoptosis pathway (caspases 9/3), triggered by mitochondrial damage, and to pyroptosis (caspase 1) through the inflammasome assembly. The inflammatory phenotype in MKD seems principally caused by the shortage of isoprenoid compounds, sensed as an alarming metabolic dysregulation, even if it is still unknown precisely how a depletion of FPP or GGPP could activate the inflammasome. One likely factor is aberrant activity of small GTPases. In the context of MKD, the small GTPase Rac1 has been identified as a mediator for the IL1β hypersecretion. Rac1, with reduced prenylation, is more active in MKD cell culture models. Inhibition of Rac1 in THP-1 monocyte cultures leads to normalization of IL1β levels [2]. Inactive RhoA leads to activation of Rac1 and PKB, thereby contributing to IL1b gene transcription and thus to the pathogenesis of MKD [3]. Moreover, the dysfunction of mitochondria could be potentially involved in MKD through the release of ROS and defective autophagy [4]. Thus there are several characteristic biochemical hallmarks of MKD that cannot be explained by abnormal activity of Rac1 or RhoA alone. On the light of this, we hypothesize that other aberrant unprenylated proteins could be responsible for the still neglected neurological aspects of MKD and for its fundamental biochemical hallmarks. Further research in this field is therefore needed.