Unfolded protein response is activated in Lewy body dementias

J. H. Baek, D. Whitfield, D. Howlett, P. Francis, E. Bereczki, C. Ballard, T. Hortobágyi, J. Attems, D. Aarsland

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 (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). Results: 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. Conclusion: 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.

Original languageEnglish
JournalNeuropathology and Applied Neurobiology
DOIs
Publication statusAccepted/In press - 2015

Fingerprint

Unfolded Protein Response
Lewy Body Disease
Synucleins
Alzheimer Disease
Dementia
Immunoglobulins
Gyrus Cinguli
Carrier Proteins
Protein Binding
Parietal Lobe
Pathology
Endoplasmic Reticulum
Parkinson Disease
Lewy Bodies
Endoplasmic Reticulum Stress
Defense Mechanisms
Temporal Lobe
Prefrontal Cortex
Protein Kinases
Western Blotting

Keywords

  • Dementia with Lewy bodies
  • Endoplasmic reticulum stress
  • GRP78/BiP
  • Parkinson's disease with dementia
  • Unfolded protein response

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Neurology
  • Histology
  • Physiology (medical)

Cite this

Baek, J. H., Whitfield, D., Howlett, D., Francis, P., Bereczki, E., Ballard, C., ... Aarsland, D. (Accepted/In press). Unfolded protein response is activated in Lewy body dementias. Neuropathology and Applied Neurobiology. https://doi.org/10.1111/nan.12260

Unfolded protein response is activated in Lewy body dementias. / Baek, J. H.; Whitfield, D.; Howlett, D.; Francis, P.; Bereczki, E.; Ballard, C.; Hortobágyi, T.; Attems, J.; Aarsland, D.

In: Neuropathology and Applied Neurobiology, 2015.

Research output: Contribution to journalArticle

Baek, JH, Whitfield, D, Howlett, D, Francis, P, Bereczki, E, Ballard, C, Hortobágyi, T, Attems, J & Aarsland, D 2015, 'Unfolded protein response is activated in Lewy body dementias', Neuropathology and Applied Neurobiology. https://doi.org/10.1111/nan.12260
Baek, J. H. ; Whitfield, D. ; Howlett, D. ; Francis, P. ; Bereczki, E. ; Ballard, C. ; Hortobágyi, T. ; Attems, J. ; Aarsland, D. / Unfolded protein response is activated in Lewy body dementias. In: Neuropathology and Applied Neurobiology. 2015.
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AU - Whitfield, D.

AU - Howlett, D.

AU - Francis, P.

AU - Bereczki, E.

AU - Ballard, C.

AU - Hortobágyi, T.

AU - Attems, J.

AU - Aarsland, D.

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AB - 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 (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). Results: 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. Conclusion: 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.

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KW - Unfolded protein response

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