Linking metabolism and RNA biology in neurodevelopment through a new pathway

Descripción del proyecto

Regulación metabólica en los trastornos del neurodesarrollo

Los trastornos del neurodesarrollo (TND) surgen debido a alteraciones en el desarrollo encefálico que afectan a las capacidades cognitivas. Estudios recientes sugieren que las mitocondrias y el metabolismo disfuncionales desempeñan un papel fundamental en los TND. La formación de circuitos neuronales requiere una elevada actividad metabólica, pero los procesos moleculares que mantienen la homeostasis metabólica siguen siendo poco conocidos. El equipo del proyecto MetaboSplicing, que cuenta con el apoyo de las Acciones Marie Skłodowska-Curie, se centra en NUAK1, una cinasa asociada al autismo, conocida por regular el metabolismo mitocondrial en las neuronas e influir en la morfogénesis de los axones. En este proyecto se explora cómo NUAK1 controla los procesos metabólicos a través de un nuevo sustrato identificado. Los hallazgos del equipo del proyecto pueden ayudar a identificar nuevas dianas terapéuticas para los TND.

Objetivo

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.