Speaker: Professor Andreas Prokop, University of Manchester
Title: Bringing meaningful order into the genetic landscape of neurodegenerative disorders
Abstract: Inherited forms of neurodegeneration – often even the same class of neurodegenerative disorder – can have links to a broad range of genes that may relate to cellular processes as diverse as transcription regulation, mitochondrial function, metabolism or cytoskeletal regulation. Of these, especially the recessive mutations suggest some form of interconnectedness that aligns such diverse functions towards a common outcome. Our research provides explanations. We focus on nerve fibres (aka axons), the cable-like processes of neurons wiring nervous systems. These delicate, often meter-long structures need to persist and function for a century, rendering them prominent initiation sites of degeneration. Studying axons of Drosophila primary neurons as efficient experimental system providing the required genetic power, we manipulated and analysed over 100 genes in standardised ways. About 40% share a characteristic ‘microtubule curling’ phenotypes (similarly observed in humans), which we take as a proxy for axon pathology. We can classify these genes by function to cause either ROS-dependent curling through affecting ‘physiological homeostasis’ or ROS-independent curling through disturbing ‘structural homeostasis’. We propose the ‘dependency cycle of local axon homeostasis’ as unifying concept which can explain why different genes can cause the same disorder class – but also why ageing is the biggest risk factor.