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Neurochemical Research

Neurochemical Research

IF: 3.7
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Chaperone-Mediated Autophagy Alleviates Cerebral Ischemia-Reperfusion Injury by Inhibiting P53-Mediated Mitochondria-Associated Apoptosis.

Published:22 November 2024 DOI: 10.1007/s11064-024-04266-x
Shaonan Yang, Lu Jiang, Ling Deng, Jingjing Luo, Xiaoling Zhang, Sha Chen, Zhi Dong

Abstract

Ischemia–reperfusion is a complex brain disease involving multiple biological processes, including autophagy, oxidative stress, and mitochondria-associated apoptosis. Chaperone-mediated autophagy (CMA), a selective autophagy, is involved in the development of various neurodegenerative diseases and acute nerve injury, but its role in ischemia–reperfusion is unclear. Here, we used middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen–glucose deprivation/reoxygenation (OGD/R) models to simulate cerebral ischemic stroke in vivo and in vitro, respectively. LAMP2A (lysosome-associated membrane protein 2A), a key molecule of CMA, was dramatically downregulated in ischemia–reperfusion. Enhancement of CMA activity by LAMP2A overexpression reduced the neurological deficit, brain infarct volume, pathological features, and neuronal apoptosis of the cortex in vivo. Concomitantly, enhanced CMA activity alleviated OGD/R-induced apoptosis and mitochondrial membrane potential decline in vitro. In addition, we found that CMA inhibited the P53(Tumor protein p53) signaling pathway and reduced P53 translocation to mitochondria. The P53 activator, Nutlin-3, not only reversed the inhibitory effect of CMA on apoptosis, but also significantly weakened the protective effect of CMA on OGD/R and MCAO/R. Taken together, these results indicate that inhibition of P53-mediated mitochondria-associated apoptosis is essential for the neuroprotective effect of CMA against ischemia–reperfusion.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
NUTLIN-3 548472-68-0 C30H30Cl2N4O4 192 suppliers $35.24-$3205.00
NUTLIN-3 548472-68-0 C30H30Cl2N4O4 192 suppliers $35.24-$3205.00
NUTLIN-3 548472-68-0 C30H30Cl2N4O4 192 suppliers $35.24-$3205.00
NUTLIN-3 548472-68-0 C30H30Cl2N4O4 192 suppliers $35.24-$3205.00

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