Linking metabolism and RNA biology in neurodevelopment through a new pathway

Descrizione del progetto

Regolazione metabolica nei disturbi del neurosviluppo

I disturbi del neurosviluppo emergono a causa di alterazioni dello sviluppo cerebrale che influiscono sulle capacità cognitive. Studi recenti suggeriscono che i mitocondri e il metabolismo disfunzionali svolgono un ruolo chiave in questo tipo di disturbi. La formazione dei circuiti neuronali richiede un’elevata attività metabolica, ma i processi molecolari che mantengono l’omeostasi metabolica restano poco conosciuti. Con il sostegno del programma di azioni Marie Skłodowska-Curie, il progetto MetaboSplicing si concentra su NUAK1, una chinasi associata all’autismo, nota per regolare il metabolismo mitocondriale nei neuroni e per influenzare la morfogenesi degli assoni. Il progetto esplora come NUAK1 controlla i processi metabolici attraverso un nuovo substrato identificato. I risultati potrebbero contribuire a identificare nuovi bersagli terapeutici per i disturbi del neurosviluppo.

Obiettivo

Neurodevelopmental disorders (NDDs) affect 3-8 percent of children across Europe and cause a life-long alteration of cognitive abilities or social interactions with little therapeutic possibilities. Recent studies have uncovered that dysfunctional mitochondria and metabolism are involved in NDDs like intellectual disability and autism spectrum disorder. Notably, neuronal circuit development, a crucial process during the formation of the brain, is characterized by an increase in metabolic activity supporting a period of intense remodelling. However, the knowledge of molecular processes controlling metabolic homeostasis during neural circuit development is still incomplete. We recently defined the autism-associated kinase NUAK1 as a critical regulator of local mitochondrial metabolism in neurons, supporting axon morphogenesis. However it is not clear how NUAK1 controls metabolic processes in neurons. We have identified a novel substrate of NUAK1 and hypothesize that NUAK1 controls an alternative splicing program through this new interactor, thereby regulating metabolism, which in turn affects neuronal development. We will: 1. Perform a phenotypical characterization of the novel substrates role in developing neurons in vitro and in vivo; 2. Investigate its effect on neuronal and axonal metabolism; 3. Characterize its associated transcriptomic signature in developing neurons; and 4. Assess the role of NUAK1 in controlling its novel substrate functionally. For this, we will use state-of-the-art techniques like microfluidic devices and deep-sequencing of mRNA. This ambitious project aspires to describe a new cellular pathway, integrating RNA biology and metabolism in developing neurons and will provide the first characterization of a novel interactor of NUAK1 and its control by the latter in developing neurons.