Inhibition of the PERK-Dependent Unfolded Protein Response Signaling Pathway Involved in the Pathogenesis of Alzheimer's Disease. Rozpędek, W., Pytel, D., Popławski, T., Walczak, A., Gradzik, K., Wawrzynkiewicz, A., Wojtczak, R., Mucha, B., Diehl, J. A., & Majsterek, I. Current Alzheimer Research, 16(3):209–218, 2019.
doi  abstract   bibtex   
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.
@article{rozpedek_inhibition_2019,
	title = {Inhibition of the {PERK}-{Dependent} {Unfolded} {Protein} {Response} {Signaling} {Pathway} {Involved} in the {Pathogenesis} of {Alzheimer}'s {Disease}},
	volume = {16},
	issn = {1875-5828},
	doi = {10.2174/1567205016666190228121157},
	abstract = {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.},
	language = {eng},
	number = {3},
	journal = {Current Alzheimer Research},
	author = {Rozpędek, Wioletta and Pytel, Dariusz and Popławski, Tomasz and Walczak, Anna and Gradzik, Kinga and Wawrzynkiewicz, Adam and Wojtczak, Radosław and Mucha, Bartosz and Diehl, John Alan and Majsterek, Ireneusz},
	year = {2019},
	pmid = {30819079},
	keywords = {Alzheimer's disease, PERK, PERK inhibitors, apoptosis, eIF2α, neurodegeneration.},
	pages = {209--218}
}

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