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J Cereb Blood Flow Metab. 2019 Sep;39(9):1836-1848. doi: 10.1177/0271678X18769770. Epub 2018 Apr 16.

The AAA + ATPase Thorase is neuroprotective against ischemic injury.

Author information

1
1 Neuroregeneration and Stem Cell Programs Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
2
2 Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
3
3 Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China.
4
4 Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University Baltimore, MD, USA.
5
5 Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University Baltimore, MD, USA.
6
6 Physiology, School of Medicine, Johns Hopkins University Baltimore, MD, USA.

Abstract

Neuronal preconditioning in vitro or in vivo with a stressful but non-lethal stimulus leads to new protein expression that mediates a profound neuroprotection against glutamate excitotoxicity and experimental stroke. The proteins that mediate neuroprotection are relatively unknown and under discovery. Here we find that the expression of the AAA + ATPase Thorase is induced by preconditioning stimulation both in vitro and in vivo. Thorase provides neuroprotection in an ATP-dependent manner against oxygen-glucose deprivation (OGD) neurotoxicity or glutamate N-Methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity in vitro. Knock-down of Thorase prevents the establishment of preconditioning induced neuroprotection against OGD or NMDA neurotoxicity. Transgenic overexpression of Thorase provides neuroprotection in vivo against middle cerebral artery occlusion (MCAO)-induced stroke in mice, while genetic deletion of Thorase results in increased injury in vivo following stroke. These results define Thorase as a neuroprotective protein and understanding Thorase signaling could offer a new therapeutic strategy for the treatment of neurologic disorders.

KEYWORDS:

AAA + ATPase; ATAD1; neuroprotection; preconditioning; stroke

PMID:
29658368
PMCID:
PMC6727130
[Available on 2020-09-01]
DOI:
10.1177/0271678X18769770

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