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Unfolded protein response is activated in L ewy body dementias
Author(s) -
Baek JeanHa,
Whitfield David,
Howlett David,
Francis Paul,
Bereczki Erika,
Ballard Clive,
Hortobágyi Tibor,
Attems Johannes,
Aarsland Dag
Publication year - 2016
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12260
Subject(s) - unfolded protein response , microbiology and biotechnology , chemistry , neuroscience , medicine , biology , endoplasmic reticulum
Aim 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. Methods The level of a key mediator of the UPR pathway, glucose‐regulated protein 78 ( GRP 78), also known as binding immunoglobulin protein ( BiP ), was measured in post mortem brain tissue of patients with dementia with L ewy bodies ( DLB ) and P arkinson's disease dementia ( PDD ) in comparison with A lzheimer's disease ( AD ) and age‐matched controls using W estern blot. The UPR activation was further confirmed by immunohistochemical detection of GRP 78/ BiP and phosphorylated protein kinase RNA ‐like endoplasmic reticulum ( ER ) kinase ( p‐PERK ). Results GRP 78/ 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 GRP 78/ BiP level and α‐synuclein pathology in the cingulate gyrus, while AD ‐type pathology showed an inverse correlation relationship in the parietal cortex. Conclusion Overall, these results give emphasis to the role of UPR in L ewy body dementias, and suggest that L ewy 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.