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.

中文翻译：

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C9orf72额颞叶痴呆中未折叠的蛋白质反应激活与颗粒细胞中的二肽病理和颗粒空泡变性有关

C9orf72 中的重复扩展基因是额颞叶痴呆（C9-FTD）最普遍的遗传原因。几项研究表明未折叠蛋白反应 (UPR) 参与 C9-FTD。在人类神经病理学中，UPR 标志物与颗粒空泡变性 (GVD) 密切相关。在这项研究中，我们旨在评估 UPR 标记物的存在以及 C9-FTD 病例和神经系统健康对照的死后脑组织中二肽病理学和 GVD 的存在。我们使用免疫组织化学评估了 C9-FTD（n = 18）和对照（n = 9）病例的额叶皮层、海马和小脑中磷酸化 PERK、IRE1α 和 eIF2α 的存在。将 UPR 激活标记的存在与 pTDP-43、p62 和二肽重复 (DPR) 蛋白 (poly(GA)、-(GR) 和 ‐(GP)) 以及酪蛋白激酶 1 delta (CK1δ)，GVD 的标志物。与对照病例相比，在 C9-FTD 的海马和小脑中观察到 UPR 标记物的存在增加。在海马体中，C9-FTD 中 pPERK 和 peIF2α 的总体水平较高，包括齿状回 (DG) 的颗粒细胞。在 C9-FTD 的小脑颗粒细胞中也观察到 UPR 标志物。此外，在 C9-FTD 的海马 DG 和小脑颗粒层中的颗粒细胞中观察到 CK1δ 水平增加。双标记实验表明 UPR 标记物与二肽病理学以及 GVD 的存在之间存在很强的关联。我们得出结论，UPR 标记在 C9-FTD 中增加，并且它们的存在与二肽病理学和 GVD 相关。