Human tauopathies are not associated with an activated unfolded protein response

Abstract

Tauopathies are the neurodegenerative diseases associated with the accumulation of misfolded tau protein. Despite many years of investigation, the mechanisms underpinning tau dependent proteinopathy remains to be elucidated. A protein quality control pathway within the endoplasmic reticulum (ER), called unfolded protein response (UPR), has been suggested as a possible response implicated in the misfolded tau-mediated neurodegeneration. However, the question arose: how does the cytosolic protein tau that does not enter the ER induce a response stemming from this compartment? In this study we investigated three different human tauopathies to establish whether these diseases are associated with the activation of UPR. We probed for the modulation of several reliable UPR markers in mRNA and proteins extracted from 20 brain samples from Alzheimer's disease (AD) patients, 11 from Pick's disease (PiD) and 10 from Progressive Supranuclear Palsy (PSP) patients coupled to equal numbers of age-matched non-demented controls. This showed that different markers of UPR are not changed in any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls. These data from human tissue further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a diseased associated activation of UPR.Acknowledgements Brain tissue was provided by the London Neurodegenerative Diseases Brain Bank (LNDBB), the South West Dementia Brain Bank (SWDBB) and the Oxford Brain Bank (OBB).