ArticleBrain pathology (Zurich, Switzerland)2021
Unfolded protein response activation in C9orf72 frontotemporal dementia is associated with dipeptide pathology and granulovacuolar degeneration in granule cells.
Article in Brain pathology (Zurich, Switzerland), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
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- CREB3 gain of function variants protect against ALS.Nature communications · 2025Article
- Artificial enforcement of the unfolded protein response reduces disease features in multiple preclinical models of ALS/FTD.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Homeostasis control in health and disease by the unfolded protein response.Nature reviews. Molecular cell biology · 2025Review
- Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy.Acta neuropathologica · 2024Article
- Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier.MedComm · 2024Review
- ALS' Perfect Storm:Cells · 2024Review
- Molecular Chaperones' Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis.Cells · 2023Review
- Staufen Impairs Autophagy in Neurodegeneration.Annals of neurology · 2023Article
- Granulovacuolar degeneration bodies are independently induced by tau and α-synuclein pathology.Alzheimer's research & therapy · 2022Article
- PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS/FTD.Acta neuropathologica · 2022Article
- Review
- Towards Understanding the Relationship Between ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis.Frontiers in aging neuroscience · 2022Review
- The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations.Frontiers in molecular neuroscience · 2022Review
- The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS.Frontiers in cellular neuroscience · 2021Review
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
A repeat expansion in the C9orf72 gene is the most prevalent genetic cause of frontotemporal dementia (C9-FTD). Several studies have indicated the involvement of the unfolded protein response (UPR) in C9-FTD. In human neuropathology, UPR markers are strongly associated with granulovacuolar degeneration (GVD). In this study, we aim to assess the presence of UPR markers together with the presence of dipeptide pathology and GVD in post mortem brain tissue from C9-FTD cases and neurologically healthy controls. Using immunohistochemistry we assessed the presence of phosphorylated PERK, IRE1α and eIF2α in the frontal cortex, hippocampus and cerebellum of C9-FTD (n = 18) and control (n = 9) cases. The presence of UPR activation markers was compared with the occurrence of pTDP-43, p62 and dipeptide repeat (DPR) proteins (poly(GA), -(GR) & -(GP)) as well as casein kinase 1 delta (CK1δ), a marker for GVD. Increased presence of UPR markers was observed in the hippocampus and cerebellum in C9-FTD compared to control cases. In the hippocampus, overall levels of pPERK and peIF2α were higher in C9-FTD, including in granule cells of the dentate gyrus (DG). UPR markers were also observed in granule cells of the cerebellum in C9-FTD. In addition, increased levels of CK1δ were observed in granule cells in the DG of the hippocampus and granular layer of the cerebellum in C9-FTD. Double-labelling experiments indicate a strong association between UPR markers and the presence of dipeptide pathology as well as GVD. We conclude that UPR markers are increased in C9-FTD and that their presence is associated with dipeptide pathology and GVD. Increased presence of UPR markers and CK1δ in granule cells in the cerebellum and hippocampus could be a unique feature of C9-FTD.
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