Microtubules Deform the Nuclear Membrane and Disrupt Nucleocytoplasmic Transport in Tau-Mediated Frontotemporal Dementia

Francesco Paonessa,Lewis D Evans,Ravi Solanki,Delphine Larrieu,Selina Wray,John Hardy,Stephen P Jackson,Frederick J Livesey

doi:10.1016/j.celrep.2018.12.085

Abstract

SummaryThe neuronal microtubule-associated protein tau, MAPT, is central to the pathogenesis of many dementias. Autosomal-dominant mutations in MAPT cause inherited frontotemporal dementia (FTD), but the underlying pathogenic mechanisms are unclear. Using human stem cell models of FTD due to MAPT mutations, we find that tau becomes hyperphosphorylated and mislocalizes to cell bodies and dendrites in cortical neurons, recapitulating a key early event in FTD. Mislocalized tau in the cell body leads to abnormal microtubule movements in FTD-MAPT neurons that grossly deform the nuclear membrane. This results in defective nucleocytoplasmic transport, which is corrected by microtubule depolymerization. Neurons in the post-mortem human FTD-MAPT cortex have a high incidence of nuclear invaginations, indicating that tau-mediated nuclear membrane dysfunction is an important pathogenic process in FTD. Defects in nucleocytoplasmic transport in FTD point to important commonalities in the pathogenic mechanisms of tau-mediated dementias and ALS-FTD due to TDP-43 and C9orf72 mutations.

Highlights

The microtubule-associated protein tau (MAPT; tau) is involved in the pathogenesis of several different forms of dementia, including Alzheimer’s disease (AD), progressive supranuclear palsy, Pick’s disease, corticobasal degeneration, and frontotemporal dementia (FTD) (Lee et al, 2001; Spillantini and Goedert, 2013)
To address the question of how MAPT mutations lead to neuronal dysfunction and neurodegeneration, we investigated the effects of two different classes of MAPT mutations on the cell biology of human induced pluripotent stem cells (iPSCs)-derived cortical neurons
Increased Phosphorylation and Altered Cellular Localization of Tau in FTD-MAPT Neurons To study the effects on neuronal cell biology of FTD-MAPT mutations, we generated excitatory cortical neurons (Shi et al, 2012b) from induced pluripotent stem cells derived from individuals with different autosomal-dominant mutations in MAPT that are causal for early-onset FTD (Figures 1 and S1)

Summary

Introduction

The microtubule-associated protein tau (MAPT; tau) is involved in the pathogenesis of several different forms of dementia, including Alzheimer’s disease (AD), progressive supranuclear palsy, Pick’s disease, corticobasal degeneration, and frontotemporal dementia (FTD) (Lee et al, 2001; Spillantini and Goedert, 2013). It is well established that these mutations lead to hyperphosphorylation and aggregation of tau protein in vivo (Ballatore et al., 2007; Goedert et al, 2012), the cell biology of neuronal dysfunction and progressive neurodegeneration in this condition are currently not fully understood. Mislocalization and aggregation of tau in neuronal cell bodies are common features of tau-mediated dementias, including FTD and AD (Fu et al, 2016; Thies and Mandelkow, 2007; Zempel and Mandelkow, 2015). How MAPT mutations lead to tau hyperphosphorylation and mislocalization, the effects of this mislocalization on neuronal cell biology, and how this contributes to neuronal dysfunction and neurodegeneration all remain poorly understood

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