Frontotemporal dementia mutant tau (P301L) locks Fyn in an open, active conformation conducive to nanoclustering

Fyn is a Src kinase that controls critical signalling cascades and its postsynaptic enrichment underpins synaptotoxicity in Alzheimer’s disease (AD) and frontotemporal dementia (FTLD-tau). Previously, we found that pathogenic FTLD tau mutant (P301L) expression promotes aberrant trapping of Fyn in nanoclusters within hippocampal dendrites via an unknown mechanism (Padmanabhan et al., 2019). Here, we imaged Fyn-mEos2 using single particle tracking photoactivated localization microscopy (sptPALM) to demonstrate that nanoclustering of Fyn in hippocampal dendrites is promoted by Fyn’s open, primed conformation. Disrupting the auto-inhibitory, closed conformation of Fyn through phospho-inhibition, and perturbation of Fyn’s SH3 domain increases, Fyn’s nanoscale trapping. However, inhibition of Fyn’s catalytic domain has no impact on its mobility. Tau-P301L promotes Fyn lateral trapping via Fyn opening and ensuing increased catalytic activation. Pathogenic tau may therefore drive synaptotoxicity by locking Fyn in an open, catalytically active conformation, leading to postsynaptic entrapment and aberrant signalling cascades.