Binding of Tau to Heat Shock Protein 27 Leads to Decreased Concentration of Hyperphosphorylated Tau and Enhanced Cell Survival

Hideki Shimura,Yuko Miura-Shimura,Kenneth S Kosik

doi:10.1074/jbc.m400351200

Hideki Shimura, Yuko Miura-Shimura + Show 1 more

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https://doi.org/10.1074/jbc.m400351200

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Abstract

Pathological hyperphosphorylated tau is the principal component of paired helical filaments, a pathological hallmark of Alzheimer disease (AD) and a strong candidate for a neurotoxic role in AD and other neurodegenerative disorders. Here we show that heat shock protein 27 (Hsp27) preferentially binds pathological hyperphosphorylated tau and paired helical filaments tau directly but not non-phosphorylated tau. The formation of this complex altered the conformation of pathological hyperphosphorylated tau and reduced its concentration by facilitating its degradation and dephosphorylation. Moreover, Hsp27 rescues pathological hyperphosphorylated tau-mediated cell death. Therefore, Hsp27 is likely to provide a neuroprotective effect in AD and other tauopathies.

Highlights

Tau is a microtubule-associated protein expressed mainly in neurons where it has a role in the assembly and stability of the microtubule network
Human brain homogenates were passed over an affinity column with nickel beads coupled to recombinant four-repeat His-tau phosphorylated by GSK-3␤, and associated proteins were eluted with 1 M NaCl
A 27-kDa Coomassie Brilliant Blue (CBB) band was identified by mass spectrometry to contain the sequence VSLDVNHFAPDELTVK, which exactly matched the sequence of heat shock protein 27 (Hsp27) (Fig. 1A)

Summary

Introduction

Tau is a microtubule-associated protein expressed mainly in neurons where it has a role in the assembly and stability of the microtubule network. Tau is strongly linked to several neurodegenerative disorders as the principal pathological component of the filamentous inclusions found in the brains of AD1 patients and in a variety of diseases collectively called “tauopathies,” including progressive supranuclear palsy, Pick disease, and corticobasal degeneration [1]. These diseases often are sporadic, the tau gene can harbor mutations that lead to diverse clinical phenotypes collectively grouped under the designation frontotemporal dementia with parkinsonism linked to chromosome 17 [2]. We show that Hsp, one of the small heat shock proteins, directly associated with hyperphosphorylated recombinant tau and PHF tau from the AD brain and can rescue cell death caused by pathological hyperphosphorylated tau

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