The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease

Stutzbach, Lauren D and Xie, Sharon X and Naj, Adam C and Albin, Roger and Gilman, Sid and Lee, Virginia MY and Trojanowski, John Q and Devlin, Bernie and Schellenberg, Gerard D (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathologica Communications, 1 (1).

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Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified <jats:italic>EIF2AK3</jats:italic> as a risk factor for PSP. <jats:italic>EIF2AK3</jats:italic> encodes PERK, part of the endoplasmic reticulum’s (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR <jats:italic>PERK</jats:italic> activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated <jats:italic>EIF2AK3</jats:italic> coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response.</jats:p> </jats:sec>

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Stutzbach, Lauren D Xie, Sharon X Naj, Adam C Albin, Roger Gilman, Sid Lee, Virginia MY Trojanowski, John Q Devlin, Bernie devlinbj@pitt.edu DEVLINBJ Schellenberg, Gerard D
Date:	December 2013
Date Type:	Publication
Journal or Publication Title:	Acta Neuropathologica Communications
Volume:	1
Number:	1
Publisher:	Springer Science and Business Media LLC
DOI or Unique Handle:	10.1186/2051-5960-1-31
Schools and Programs:	School of Medicine > Psychiatry
Refereed:	Yes
Date Deposited:	29 Sep 2016 20:00
Last Modified:	05 Sep 2021 14:55
URI:	http://d-scholarship.pitt.edu/id/eprint/29709

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