Neurobiology in the bilayer: rhomboid proteases at synapses

Membrane proteins play a vital role in cell-cell signalling at the plasma membrane, requiring precise control of their activity, abundance, and localization. One powerful and irreversible way to regulate these proteins is through intramembrane proteolysis, a post-translational mechanism that, when disrupted, contributes to neurodegenerative diseases like Alzheimer’s and Parkinson’s (via dysfunction in intramembrane proteases such as gamma-secretase and PARL, respectively). Among this type of protease, secretase rhomboids stand out as highly expressed in neurons and essential for life, yet their specific roles in neuronal function remain a mystery. In this lecture, Adam will reveal how his lab is unravelling this mystery using a multidisciplinary approach, including AlphaFold2/3 modelling and molecular dynamics to explore structure-function relationships, screens to identify which proteins they cleave, and super-resolution microscopy to examine rhomboid localization and lateral diffusion at synapses.