title: Mevalonate kinase deficiency and neuroinflammation: balance between apoptosis and pyroptosis.
abstract: Mevalonic aciduria, a rare autosomal recessive disease, represents the most severe form of the periodic fever, known as Mevalonate Kinase Deficiency. This disease is caused by the mutation of the MVK gene, which codes for the enzyme mevalonate kinase, along the cholesterol pathway. Mevalonic aciduria patients show recurrent fever episodes with associated inflammatory symptoms, severe neurologic impairments, or death, in early childhood. The typical neurodegeneration occurring in mevalonic aciduria is linked both to the intrinsic apoptosis pathway (caspase-3 and -9), which is triggered by mitochondrial damage, and to pyroptosis (caspase-1). These cell death mechanisms seem to be also related to the assembly of the inflammasome, which may, in turn, activate pro-inflammatory cytokines and chemokines. Thus, this particular molecular platform may play a crucial role in neuroinflammation mechanisms. Nowadays, a specific therapy is still lacking and the pathogenic mechanisms involving neuroinflammation and neuronal dysfunction have not yet been completely understood, making mevalonic aciduria an orphan drug disease. This review aims to analyze the relationship among neuroinflammation, mitochondrial damage, programmed cell death, and neurodegeneration. Targeting inflammation and degeneration in the central nervous system might help identify promising treatment approaches for mevalonic aciduria or other diseases in which these mechanisms are involved.
authors.affiliation: Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, Trieste 34128, Italy. annalisa.marcuzzi@burlo.trieste.it.
authors.forename: Paola Maura
authors.initials: PM
authors.lastname: Tricarico
authors.forename: Annalisa
authors.initials: A
authors.lastname: Marcuzzi
authors.forename: Elisa
authors.initials: E
authors.lastname: Piscianz
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Monasta
authors.forename: Sergio
authors.initials: S
authors.lastname: Crovella
authors.forename: Giulio
authors.initials: G
authors.lastname: Kleiner
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002490:Central Nervous System / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D054078:Mevalonate Kinase Deficiency / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D018384:Oxidative Stress; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism
chemical_list: D058847:Inflammasomes; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D020169:Caspases