ELAV/Hu proteins comprise a family of highly conserved neuronal RNA binding proteins important for the development of the nervous system and for neuronal functions. Aberrant regulation of their activity or expression results in a range of neurological phenotypes including learning deficits, epilepsy, synaptic growth defects and neurodegeneration in model organisms. In humans, ELAV/Hu proteins have been associated with schizophrenia, Alzheimer’s and Parkinson’s disease. ELAV/Hu proteins are gene-specific regulators of alternative splicing of mRNAs, but can also affect other aspects of the maturation of an mRNA and its cytoplasmic expression into a protein.
Intriguingly, human Hu proteins can substitute for ELAV in a Drosophila model for alternative splicing regulation. Since ELAV/Hu proteins bind short U-rich motifs embedded in a highly degenerate sequence context, it is thought that multimerization of ELAV/Hu proteins is key to generate target specificity and that this step is highly regulated by cellular signaling. Indeed, ELAV/Hu proteins have numerous sites for post-translational modifications. From initial studies on human Hu proteins, we anticipate that altering phosphorylation will impact dramatically on ELAV function and will generate neurological phenotypes. We aim to dissect how ELAV activity is regulated by phosphorylation in Drosophila genetic and cell culture cell models for neurodegeneration. To obtain mechanistic insights into how phosphorylation impacts on alternative splicing regulation we will combine available structural information for molecular modelling of ELAV multimerization and RNA binding to instruct experimental validation.
Key experimental skills involved:
This project will incorporate a wide range of molecular and cell biology techniques, which will be applied by using the genetic model organism Drosophila and various cell culture models. The project will make use of state-of-the-art cellular imaging to study ELAV function in cells. Further, this project will apply statistical analysis of data and we willl use molecular modelling of available structural information to make predictions how phosphorylations impacts on ELAV multimerization and RNA binding.
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