Uncovering the interplay of synaptic activity and TDP-43 pathology in neurodegeneration

TDP-43 pathology and altered states of synaptic activity are defining hallmarks of Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Alzheimer’s Disease (AD), yet it remains unclear how these features interconnect to drive neurodegeneration. This project proposes that TDP-43 dysfunction and abnormal states of synaptic activity are tightly interlinked, forming a feedforward loop that exacerbates their respective pathological states. The project will first characterise how progressive TDP-43 pathology drives evolving states of synaptic activity, arising from both loss- and gain- of-function mechanisms. Advanced electrophysiological approaches in human neurons will be leveraged to examine individual synapses through to emergent network dysfunction and combined with detailed synaptic profiling to uncover molecular mechanisms driving altered activity states. Subsequently, the project will characterise how synaptic activity in turn modulates TDP-43, first focussing on how acute synaptic activity regulates phase separation and condensation of physiological TDP-43, leading to altered protein interactions and downstream RNA processing. Subsequently the project will focus on how these processes deteriorate into pathological states, exploring how chronically dysregulated synaptic activity exacerbates existing pathological conditions of mis-localised TDP-43. Together, this work aims to define a feedforward loop between TDP-43 and synaptic activity that underpins neuronal vulnerability in neurodegenerative disease.