Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment.

Peter Dongmin Sohn,Li Gan,Lea T Grinberg,William W Seeley,Yungui Zhou,Tara E Tracy,Bruce L Miller,Renata E P Leite,Hye-In Son

doi:10.1186/s13024-016-0109-0

Abstract

BackgroundNeurons are highly polarized cells in which asymmetric axonal-dendritic distribution of proteins is crucial for neuronal function. Loss of polarized distribution of the axonal protein tau is an early sign of Alzheimer’s disease (AD) and other neurodegenerative disorders. The cytoskeletal network in the axon initial segment (AIS) forms a barrier between the axon and the somatodentritic compartment, contributing to axonal retention of tau. Although perturbation of the AIS cytoskeleton has been implicated in neurological disorders, the molecular triggers and functional consequence of AIS perturbation are incompletely understood.ResultsHere we report that tau acetylation and consequent destabilization of the AIS cytoskeleton promote the somatodendritic mislocalization of tau. AIS cytoskeletal proteins, including ankyrin G and βIV-spectrin, were downregulated in AD brains and negatively correlated with an increase in tau acetylated at K274 and K281. AIS proteins were also diminished in transgenic mice expressing tauK274/281Q, a tau mutant that mimics K274 and K281 acetylation. In primary neuronal cultures, the tauK274/281Q mutant caused hyperdynamic microtubules (MTs) in the AIS, shown by live-imaging of MT mobility and fluorescence recovery after photobleaching. Using photoconvertible tau constructs, we found that axonal tauK274/281Q was missorted into the somatodendritic compartment. Stabilizing MTs with epothilone D to restore the cytoskeletal barrier in the AIS prevented tau mislocalization in primary neuronal cultures.ConclusionsTogether, these findings demonstrate that tau acetylation contributes to the pathogenesis of neurodegenerative disease by compromising the cytoskeletal sorting machinery in the AIS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0109-0) contains supplementary material, which is available to authorized users.

Highlights

Neurons are highly polarized cells in which asymmetric axonal-dendritic distribution of proteins is crucial for neuronal function
Immunoblot analyses revealed a significant decrease in levels of axon initial segment (AIS) cytoskeletal proteins, including ankyrin G (AnkG) and βIV-spectrin, in Alzheimer’s disease (AD) patients at late Braak stages compared to early Braak stages (Fig. 1b, c; Table 1)
In AD brains at late Braak stages, acetyl-K274 and -K281 on tau were detected by the acetyllysine-specific MAb359 and MAb63 tau antibodies [31], respectively

Summary

Introduction

Neurons are highly polarized cells in which asymmetric axonal-dendritic distribution of proteins is crucial for neuronal function. Consisting of microtubule (MT) bundles coated with a dense submembrane protein network containing ankyrin G (AnkG), βIV-spectrin, and actin filaments [19, 20], the AIS cytoskeleton forms a barrier between the axon and the somatodendritic membrane [21] and regulates axonal entry of cargoes that require selective transport [22]. This barrier prevents axonal tau from invading the somatodendritic compartment, pathologically modified tau can bypass the AIS and be mislocalized from the axon [23]. The AIS cytoskeleton is perturbed in AD and other neurodegenerative diseases [24,25,26]

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