Unfolded protein response activation in C9orf72 frontotemporal dementia is associated with dipeptide pathology and granulovacuolar degeneration in granule cells.
C9orf72
cerebellum
dentate gyrus
granule cells
granulovacuolar degeneration
unfolded protein response
Journal
Brain pathology (Zurich, Switzerland)
ISSN: 1750-3639
Titre abrégé: Brain Pathol
Pays: Switzerland
ID NLM: 9216781
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
01
04
2020
revised:
14
08
2020
accepted:
17
08
2020
pubmed:
1
9
2020
medline:
21
12
2021
entrez:
1
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32865835
doi: 10.1111/bpa.12894
pmc: PMC7891436
doi:
Substances chimiques
C9orf72 Protein
0
C9orf72 protein, human
0
Dipeptides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
163-173Subventions
Organisme : ZonMw
ID : Memorabel ZonMW fellowship grant to AAD, #733050507
Pays : Netherlands
Informations de copyright
© 2020 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.
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