Depletion of oxidative and endoplasmic reticulum stress regulators in Pick disease |
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| Authors: | Ekaterina V. Ilieva Alba Naudí Anton Kichev Isidre Ferrer Reinald Pamplona Manuel Portero-Otín |
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| Affiliation: | 1. Department of Experimental Medicine, University of Lleida, Lleida 25008, Spain;2. Institute of Neuropathology, Service of Pathologic Anatomy, University Hospital of Bellvitge, University of Barcelona, CIBERNED, Hospitalet de Llobregat, Barcelona 08907, Spain;1. Department of Medical Cell Biology, Medical Faculty of Uppsala University, Biomedical Centre, P.O. Box 751, SE-75123 Uppsala, Sweden;2. Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg and German Center for Diabetes Research (DZD), Heidelberg, Germany;1. Biochemistry Section, Faculty of Biochemistry and Environmental Sciences, University of Castilla-La Mancha, Toledo, Spain;2. Albacete University Hospital, Albacete, Spain;3. Genetics Section, Faculty of Biochemistry and Environmental Sciences, University of Castilla-La Mancha, Toledo, Spain;1. Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China;2. Department of Cell Biology & Genetics, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China;3. Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China;4. Department of Pathology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China;5. Department of Oncology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China;6. Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China;7. Department of Urology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China;8. Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, PR China;9. Department of Endoscopy, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi 030001, PR China;10. Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, PR China;1. Sidney Kimmel Comprehensive Cancer Center, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA;2. Sandra and Edward Meyer Cancer Center, Department of Urology, Weill Cornell Medical College, New York, NY, USA |
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| Abstract: | Both oxidative and endoplasmic reticulum (ER) stress is associated with multiple neurodegenerative, age-related diseases. The rare disorder Pick disease (PiD) shares some pathological hallmarks of other neurodegenerative diseases that may be related to oxidative stress. Importantly, activation of an ER stress response, which is also involved in aging, has not yet been investigated in PiD. In this study, we assessed the implication of ER stress associated with oxidative stress in PiD as a potential mechanism involved in its pathogenesis. Samples from morphologically affected frontal cortex and apparently pathologically preserved occipital cortex showed region-dependent increases in different protein oxidative damage pathways. The oxidative modifications targeted antioxidant enzymes, proteases, heat shock proteins, and synaptic proteins. These effects were associated with compromised proteasomal function and ER stress in frontal cortex samples. In addition, we observed a depletion in ER chaperones (glucose-regulated proteins Grp78/BiP and glucose-regulated protein 94) and differences in tissue content and distribution of nuclear factor-erythroid 2 p45-related respiratory 2, required for cell survival during the unfolded protein response. These results demonstrate increased region-specific protein oxidative damage in PiD, with proteasomal alteration and dysfunctional ER stress response. We suggest this was caused by complete and specific depletion of Grp78/BiP, contributing to the pathophysiology of this neurodegenerative disease. |
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