title: Unfolded protein response is activated in Lewy body dementias.
abstract: The unfolded protein response (UPR) is a pro-survival defence mechanism induced during periods of endoplasmic reticulum stress, and it has recently emerged as an attractive therapeutic target across a number of neurodegenerative conditions, but has not yet been studied in synuclein disorders.
  
  
  
  The level of a key mediator of the UPR pathway, glucose-regulated protein 78 (GRP78), also known as binding immunoglobulin protein (BiP), was measured in post mortem brain tissue of patients with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) in comparison with Alzheimer's disease (AD) and age-matched controls using Western blot. The UPR activation was further confirmed by immunohistochemical detection of GRP78/BiP and phosphorylated protein kinase RNA-like endoplasmic reticulum (ER) kinase (p-PERK).
  
  
  
  GRP78/BiP was increased to a greater extent in DLB and PDD patients compared with AD and control subjects in cingulate gyrus and parietal cortex. However, there were no changes in the prefrontal and temporal cortices. There was a significant positive correlation between GRP78/BiP level and α-synuclein pathology in the cingulate gyrus, while AD-type pathology showed an inverse correlation relationship in the parietal cortex.
  
  
  
  Overall, these results give emphasis to the role of UPR in Lewy body dementias, and suggest that Lewy body degeneration, in combination with AD-type pathologies, is associated with increased UPR activation to a greater extent than AD alone, possibly as a consequence of the increasing load of ER proteins. This work also highlights a novel opportunity to explore the UPR as a therapeutic target in synuclein diseases.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Division for Neurogeriatrics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Jean-Ha
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Whitfield
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Howlett
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Francis
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Division for Neurogeriatrics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Erika
authors.initials: E
authors.lastname: Bereczki
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Ballard
authors.affiliation: Department of Neuropathology, Institute of Pathology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Johannes
authors.initials: J
authors.lastname: Attems
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Division for Neurogeriatrics, Karolinska Institute, Stockholm, Sweden.|Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Aarsland
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D056811:Unfolded Protein Response; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D051844:alpha-Synuclein
keywords: GRP78/BiP; Parkinson's disease with dementia; dementia with Lewy bodies; endoplasmic reticulum stress; unfolded protein response