Role of unprenylated 2’,3’-cyclic-nucleotide 3’-phosphodiesterase in the molecular mechanisms responsible for neuroinflammation and neurological impairments in mevalonate kinase deficiency

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive disease, characterized by neurologic impairments such as psychomotor retardation, failure to thrive, progressive cerebellar ataxia, progressive visual impairment and recurrent fevers, commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. MKD is caused by a reduced activity of mevalonate kinase (MVK) that is an enzyme of the mevalonate pathway, a biosynthetic route that produces cholesterol and branched unsaturated lipid chains called non-sterol isoprenoids. Although in the past decade the knowledge of MKD pathogenesis has increased, the cause is not yet clear. To date the most accredited pathogenic hypothesis is that the typical neurodegeneration is linked to neuroinflammation, in particularly through the activation of the inflammasome which is a cytosolic, multiprotein platform able to induce just a potent inflammatory response. Central nervous system (CNS) hosts innate immune system. This includes microglia cells, the neuronal counter-part of macrophages, that in this scenario result crucial. 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 could activate the inflammasome. A less known isoprenylated protein is 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP), most abundant in the CNS. Its physiological function is still enigmatic, but may play a role in neuroprotection. On the light of this, in this research program we aim to investigate if aberrant unprenylated CNP could be responsible of the still neglected neurological aspects of MKD and of its fundamental biochemical hallmarks. The execution of the program could lead to important advances in the understanding of the pathogenesis of the disease and to the identification of CNP as a new pharmacological target.