Research Paper Volume 14, Issue 3 pp 1233—1252
PERK activation by SB202190 ameliorates amyloidogenesis via the TFEB-induced autophagy-lysosomal pathway
- 1 Department of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea
- 2 National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju 54907, Republic of Korea
- 3 Department of Food Science and Nutrition, University of Ulsan, Ulsan 44610, Republic of Korea
- 4 Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
- 5 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
- 6 Cancer Research Institute, Seoul National University, Seoul 03080, Republic of Korea
Received: August 13, 2021 Accepted: February 8, 2022 Published: February 15, 2022https://doi.org/10.18632/aging.203899
How to Cite
Copyright: © 2022 Do et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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-1α (IRE1α) 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.
PERK: protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase; UPR: unfolded protein response; ALP: autophagy-lysosome pathway; TFEB: transcription factor-EB; IRE1α: inositol-requiring transmembrane kinase/endoribonuclease-1α; ATF6: activating transcription factor 6; AD: Alzheimer’s diseases; PD: Parkinson’s diseases; HD: Huntington’s diseases; Aβ: amyloid β; ER: endoplasmic reticulum; α-syn: α-synuclein; mtROS: mitochondrial ROS; MAMs: mitochondria-associated ER membranes; Tg: thapsigargin; CsA: cyclosporin A; CQ: chloroquine.