MAMA: Molecular Analysis and manipulation of Metabolic signalling in Adenylosuccinase deficiency

Mutations in the Adenylosuccinate lyase (ADSL) gene (22q13.1) lead to a rarely diagnosed autosomal recessive disease, characterized by a purine metabolism defect, resulting in accumulation of N-succinyl-5-aminoimidazole-4-carboxamide ribonucleoside (SAICAr) and succinyladenosine (S-Ado), in body fluids. The phenotype covers a range of childhood symptoms, such as encephalopathy, psychomotor delay, autistic behaviours, seizures, muscle hypotonia and wasting, in severe (Type I), mild (Type II), and neonatal lethal form. The molecular mechanisms underlying ADSL-deficiency (ADSLd) are still obscure, and there are no clear evidence linking the metabolic defect with neurological and muscular defects. Two hypotheses have been formulated: i) neurological alterations could be related to the lack of nucleotides, affecting DNA synthesis and compromising embryonic neurodevelopment; ii) SAICAr and S-Ado, which represent “waste” metabolites resulting from ADSL-deficiency, could be toxic for the cell. Our preliminary data suggest that ADSL might indirectly control glucose metabolism, mitochondrial homeostasis, and the activity of AMPK, a critical enzyme in cellular energy production. We hypothesise here that defects of mitochondria metabolism and glucose uptake, associated with dysregulation of a catabolic process termed autophagy, may play a central role in ADSLd, by impacting both energy and metabolite availability. The main goal of MAMA would thus be the identification of the molecular mechanisms underlying ADSL ontogenesis and progression, and the establishment of cell lines and transgenic fly models (bearing patients specific mutations), as to allow testing of the efficacy of specific drugs, for the development of innovative therapeutic strategies.