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Investigating the human serinosome: relevance to brain L-serine synthesis - the SerMET project
The SerMET project
In the brain, the “phosphorylated pathway” (PP) is the main route for the synthesis of L-serine, the precursor of D-serine and glycine, two key co-agonists of NMDA receptors, which are involved in synaptic transmission and brain plasticity. This cytosolic pathway involves three enzymatic steps catalyzed by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase (PSP). In differentiated human astrocytes, these enzymes dynamically assemble into a transient metabolic complex known as the serinosome.
This project aims to explore the mechanisms controlling the formation of this complex and its functional relevance in L-serine synthesis in the central nervous system.
We aim to assess the presence of the serinosome across different biological contexts, and to investigate how neuron-astrocyte interactions influence the formation of this complex through co-culture experiments.
Next, the three PP enzymes will be recombinantly expressed in CHO mammalian cells, allowing us to reconstruct the pathway in vitro.
A key focus of the project will be PHGDH, the first enzyme in the pathway, which plays a major role in the functionality of this metabolic route. We will study disease-associated variants of PHGDH, evaluating their impact on both L-serine synthesis and serinosome integrity. The data obtained will be analyzed using multivariate approaches to develop a predictive model of how specific mutations affect the functionality of the pathway, thus allowing targeted therapeutic approaches.
Finally, we aim to identify the cellular factors and environmental stimuli that drive the assembly and disassembly of the serinosome.
This project has the potential to uncover critical insights into the maintenance of D-serine and glycine homeostasis. This is essential to better understand the modulation of NMDA receptors activity under both physiological and pathological conditions. Ultimately, our findings might guide the development of new therapeutic strategies for the treatment of neurological and metabolic disorders linked to impaired L-serine biosynthesis.
PI at The Protein Factory 2.0: Valentina Rabattoni, Loredano Pollegioni
Participants: Daniele Riva, Kainat Ulfat, Elena Rosini, Natasa Kustrimovic
Fundings: this work has been supported by Fondazione Cariplo, Bando Giovani Ricercatori 2024
Collaborations: University of Milano-Bicocca, University Hospital of Lausanne