Journal
AGING-US
Volume 14, Issue 3, Pages 1233-1252Publisher
IMPACT JOURNALS LLC
Keywords
amyloidogenesis; mitochondrial reactive oxygen species; PERK; transcription factor-EB; autophagy-lysosome pathway
Categories
Funding
- Priority Research Centers Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2014R1A6A1030318, NRF-2020R1A2C1009192, NRF-2020R1A2C1006470, NRF2021R1F1A1052424]
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In this study, the activation of PERK was found to promote ALP activation, thereby alleviating amyloidogenesis in neurodegenerative diseases.
The protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK), a key ER stress sensor of the unfolded protein response (UPR), can confer beneficial effects by facilitating the removal of cytosolic aggregates through the autophagy-lysosome pathway (ALP). In neurodegenerative diseases, the ALP ameliorates the accumulation of intracellular protein aggregates in the brain. Transcription factor-EB (TFEB), a master regulator of the ALP, positively regulates key genes involved in the cellular degradative pathway. However, in neurons, the role of PERK activation in mitigating amyloidogenesis by ALP remains unclear. In this study, we found that SB202190 selectively activates PERK independently of its inhibition of p38 mitogen-activated protein kinase, but not inositol-requiring transmembrane kinase/endoribonuclease-1 alpha (IRE1 alpha) or activating transcription factor 6 (ATF6), in human neuroblastoma cells. PERK activation by SB202190 was dependent on mitochondrial ROS production and promoted Ca2+-calcineurin activation. The activation of the PERK-Ca2+-calcineurin axis by SB202190 positively affects TFEB activity to increase ALP in neuroblastoma cells. Collectively, our study reveals a novel physiological mechanism underlying ALP activation, dependent on PERK activation, for ameliorating amyloidogenesis in neurodegenerative diseases.
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