Inhibition of the PERK-Dependent Unfolded Protein Response Signaling Pathway Involved in the Pathogenesis of Alzheimer’s Disease

Abstract

<P>Objectives: There is a body of evidence that neurodegenerative disease entities are directly correlated with the perturbations on the molecular level. Hence, the ER stress-mediated Unfolded Protein Response (UPR) is activated resulting in PERK-dependent phosphorylation of the Eukaryotic initiation factor 2 (eIF2α). Thus, the levels of ATF4 and CHOP proteins are significantly increased, which subsequently switches the pro-adaptive branch of the UPR into the pro-apoptotic directly leading to neuronal loss and initiation of the neurodegenerative process. The aim of the presented study was the evaluation of the biological activity of highly specific, small-molecule inhibitors of the PERKdependent UPR signaling pathway. Methods: The study was conducted on rat astrocytic DI TNC1 cell line. The level of p-eIF2α was measured by Western blot technique, the cytotoxicity of the investigated compound was assessed by the MTT assay and using the FITC-conjugated Annexin V (Annexin V-FITC) to indicate apoptosis and propidium iodide (PI) to indicate necrosis. The effect of tested compound on cell cycle progression was measured by flow cytometry, where the PI-labelled nuclei were analysed for DNA content. Results: As a result one of the investigated compound LDN-0060609 triggers a significant inhibition of the eIF2α phosphorylation in DI TNC1 cell line. Moreover, we showed that compound LDN-0060609 is non-cytotoxic and has no effect on cell cycle progression. Conclusion: In conclusion, LDN-0060609 may constitute a novel, targeted treatment approach against neurodegenerative diseases, including Alzheimer’s disease (AD), where pathogenesis and progression are closely associated with the overactivation of the PERK-dependent UPR signaling pathway.

Anti-proliferative bioactivity against HT-29 colon cancer cells of a withanolides-rich extract from golden berry (Physalis peruviana L.) calyx investigated by Foodomics

“…These genes are involved in resistance to cancer therapy (Tirado-Hurtado, Fajardo, & Pinto, 2018), or in the initiation of apoptotic cell death after long-term activation of the ER stress responses (Rozpędek et al, 2016). Furthermore, TRIB3 has been suggested as a novel marker for prognosis in colorectal cancer (Ohoka, Yoshii, Hattori, Onozaki, & Hayashi, 2005), and its down-regulation may explain the anti-proliferative activity of the extract.…”

The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases

“…However, the actual mechanism of action of the inhibitor is yet to be identified. It would also be intriguing to investigate whether this mentioned compound in fact exerts neuroprotective effects in animal models of not only AD but also other neurodegenerative diseases, including PD, ALS, and prion disease [289].…”

The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma

“…The newest data have reported that aggregation of misfolded and unfolded proteins within the lumen of the ER is strictly associated with the pathogenesis of multiple neurodegenerative disorders, as it may affect numerous cell signaling pathways and neuronal connectivity, and finally evoke neuronal apoptosis [298][299][300][301]. The ER constitutes a dynamic cellular organelle that plays a major role in protein synthesis, posttranslational modification, trafficking, lipids and steroids synthesis, carbohydrate metabolism, calcium homeostasis, as well as efficient drugs metabolism [302][303][304].…”

“…However, if the ER stress is severe and prolonged, the pro-adaptive branch of the UPR may switch into the pro-apoptotic one. Thus, there is ample evidence that targeting components of the UPR signaling pathway may constitute a novel, promising treatment strategy against ER stress-dependent human neurodegenerative pathologies [301,313,314].…”