Dissecting serine metabolism in the brain
PI: Loredano Pollegioni
Silvia Sacchi, Giulia Murtas, Valentina Rabattoni, Elena Zerbini
Murtas G, et al. 2020. L-serine synthesis via the phosphorylated pathway in humans. Cell Mol Life Sci. 77:5131-5148. doi: 10.1007/s00018-020-03574-z.
PRIN 2017 (Grant 2017H4J3AS) to LP
Gabriella Tedeschi (University of Milan, Milan, Italy)
Paola Coccetti (University of Milan-Bicocca, Milan, Italy)
Barbara Campanini (University of Parma, Parma, Italy)
Nadia Canu (University of Rome "Tor Vergata", Rome, Italy)
The cytosolic “phosphorylated pathway” for the de novo biosynthesis of L-serine (L-Ser) from the glycolytic intermediate 3-phosphoglycerate (3PG), is composed of three reactions catalysed by 3-phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase (PSP).
In the brain, the “phosphorylated pathway” (PP) is the primary route for the synthesis of L-Serine (L-Ser), the precursor of glycine and D-Ser, two relevant coagonists of NMDA receptors, which are critically involved in synaptic plasticity, cognitive functions and cellular excitotoxicity. Either high or low levels of D-Ser are associated with NMDA receptors dysfunction and the related cognitive deficit that occurs in normal aging and Alzheimer’s disease (AD).
In this project, we plan to investigate the PP combining different biochemical approaches to perform analysis on cell model systems and brain samples aimed to: i) characterize the structural, functional and regulatory properties of the three involved enzymes (including splicing and point variants associated to pathological conditions); ii) perform extensive proteome and metabolome analyses.
The expected results, i.e. the system biology of serine circuit, might allow the identification of new mechanisms and targets for the treatment of pathologies in which the glutamatergic system is affected.