Frontotemporal dementia mutant Tau promotes aberrant Fyn nanoclustering in hippocampal dendritic spines

Pranesh Padmanabhan,Frédéric A Meunier,Jürgen Götz,Di Xia,Ramón Martínez-Mármol

doi:10.7554/elife.45040

Abstract

The Src kinase Fyn plays critical roles in memory formation and Alzheimer's disease. Its targeting to neuronal dendrites is regulated by Tau via an unknown mechanism. As nanoclustering is essential for efficient signaling, we used single-molecule tracking to characterize the nanoscale distribution of Fyn in mouse hippocampal neurons, and manipulated the expression of Tau to test whether it controls Fyn nanoscale organization. We found that dendritic Fyn exhibits at least three distinct motion states, two of them associated with nanodomains. Fyn mobility decreases in dendrites during neuronal maturation, suggesting a dynamic synaptic reorganization. Removing Tau increases Fyn mobility in dendritic shafts, an effect that is rescued by re-expressing wildtype Tau. By contrast, expression of frontotemporal dementia P301L mutant Tau immobilizes Fyn in dendritic spines, affecting its motion state distribution and nanoclustering. Tau therefore controls the nanoscale organization of Fyn in dendrites, with the pathological Tau P301L mutation potentially contributing to synaptic dysfunction by promoting aberrant Fyn nanoclustering in spines.

Highlights

Dendritic spines compartmentalize biochemical reactions that are critical for synaptic plasticity, which underpins memory and learning
We found that Fyn mobility was spatially heterogeneous and that the diffusion coefficients of FynmEos2 molecules varied more than 100-fold in individual neurons and even within individual spines (Figure 1—figure supplement 1)
We found that Fyn mobility dramatically decreased in the dendrites of Tau knockout (Tau KO) neurons expressing TauP301L-GFP compared to those expressing TauWT-GFP, as evidenced by the changes in the average mean square displacement (MSD) (Figure 6c), the area under the MSD curves (AUC) (Figure 6d), the frequency distribution of diffusion coefficients (Figure 6e), and the immobile fraction (Figure 6f)

Summary

Introduction

Dendritic spines compartmentalize biochemical reactions that are critical for synaptic plasticity, which underpins memory and learning. The spatial organization of receptors and signaling molecules into nanodomains in biological membranes is emerging as an essential feature of cell signaling (Kusumi et al, 2012) These nanodomains are formed by a combination of protein–protein, lipid–lipid, protein–lipid and cytoskeletal interactions (Milovanovic and Jahn, 2015; Goyette and Gaus, 2017; Padmanabhan et al, 2019), as well as by membrane-mediated forces (Johannes et al, 2018). These nanodomains concentrate various molecules in discrete areas, thereby facilitating efficient and robust processing of cellular information by regulating a complex series of biochemical reactions (Harding and Hancock, 2008). Our study reveals a complex interplay between Fyn and Tau in the somatodendritic compartment and points to a novel role of altered Fyn nanoclustering in causing synaptic dysfunction in disease

Results

Discussion

Materials and methods