CNS waste disposal - molecular mechanism for controlling AQP4 localisation

The water channel aquaporin 4 (AQP4) is central to CNS water homeostasis.

It is found in the membrane of astrocyte end-feet surrounding CNS blood vessels where it plays a key role in the glymphatic waste clearance system.

This activity is increased during sleep and reduced in the ageing brain, the latter which leads to an increased vulnerability to neurodegenerative disease. Moreover, pathological water flow through AQP4 following trauma or stroke underlies the build-up of CNS edema.

As such, AQP4 has emerged as a promising candidate for pharmaceutical treatment of several disease states, including Alzheimer’s and CNS edema.We have recently shown that AQP4 is regulated by sub-cellular relocalisation in a calmodulin-dependent manner and that targeting this mechanism is viable strategy for CNS edema treatment.

Building on this discovery, this 4-year project in Susanna Törnroth-Horsefield’s group at Lund University aims to describe the protein-protein interactions that control this process and deliver structural models that can be used for drug design.

To do this, we will combine in vitro biophysical characterisation with structural characterisation of AQP4 complexes through an integrative structural biology approach.

Our work will significantly increase the understanding of AQP4 relocalisation in health and disease and establish a structural framework that can be used to translate this knowledge into effective AQP4-targeting pharmaceutical treatments.