title: Depletion of oxidative and endoplasmic reticulum stress regulators in Pick disease.
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.
authors.affiliation: Department of Experimental Medicine, University of Lleida, Lleida 25008, Spain.
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Ilieva
authors.forename: Alba
authors.initials: A
authors.lastname: Naudí
authors.forename: Anton
authors.initials: A
authors.lastname: Kichev
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otín
mesh_terms: D000368:Aged; D001344:Autopsy; D002470:Cell Survival; D003704:Dementia; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D050983:NF-E2 Transcription Factor / Q000378:metabolism; D009778:Occipital Lobe / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D020774:Pick Disease of the Brain / Q000378:metabolism* / Q000503:physiopathology; D056811:Unfolded Protein Response
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D050983:NF-E2 Transcription Factor; C018551:glucose-regulated proteins