Phosphorylation at S548 as a Functional Switch of Sterile Alpha and TIR Motif-Containing 1 in Cerebral Ischemia/Reperfus
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Phosphorylation at S548 as a Functional Switch of Sterile Alpha and TIR Motif-Containing 1 in Cerebral Ischemia/Reperfusion Injury in Rats Tao Xue 1 & Qing Sun 1 & Yijie Zhang 1 & Xin Wu 1 & Haitao Shen 1 & Xiang Li 1 & Jiang Wu 1 & Haiying Li 1 Gang Chen 1
&
Zhong Wang 1 &
Received: 20 July 2020 / Accepted: 14 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a pro-degenerative molecule in Wallerian degeneration, which is mainly expressed in brain/neurons and colocalized with mitochondria and microtubules. The aim of this study was to determine the role of SARM1 in cerebral ischemia/reperfusion (I/R) injury and the underlying mechanisms. In vivo, a middle cerebral artery occlusion/reperfusion (MCAO/R) model in adult male Sprague Dawley rats (250–300 g) was established, and in vitro, cultured primary neurons were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to imitate I/R injury. Overexpression lentiviruses encoding wild-type SARM1 and SARM1 with serine 548 alanine mutation (S548A) were constructed and administered to rats by intra-penumbral injection. First, the potential role of SARM1 in cerebral I/R injury was confirmed by the increased protein levels of SARM1 within penumbra tissue, especially in neurons. Second, there was an increase in the phosphorylation ratio of p-SARM1(S548)/SARM1 at 2 h after MCAO/R. Third, on the basis of site-specific mutagenesis, we identified S548 as a key site for SARM1 phosphorylation in I/R conditions. Fourth, SARM1 (S548A) overexpression reduced infarct size, neuronal death, and neurobehavioral dysfunction, while wild-type SARM1 overexpression had the opposite effects. Finally, we found that SARM1 phosphorylation at the S548 site switched SARM1 function from promoting mitochondrial transport to inhibiting mitochondrial transport along axons after I/R injury. Restriction of SARM1 phosphorylation at S548 may be a promising intervention target for I/R injury; thus, exogenous administration of SARM1 (S548A) may be a novel strategy for improving neurological outcomes. Keywords SARM1 . I/R injury . S548A . Mitochondrial transport . Neurological outcomes
Introduction Acute ischemic stroke, as a main kind of stroke and the leading cause of death and disability worldwide, has been Tao Xue and Qing Sun contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02132-9) contains supplementary material, which is available to authorized users. * Haiying Li [email protected] * Zhong Wang [email protected] 1
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
considered to result in frustrating outcomes despite appropriate medical treatment and care [1–4]. From the pathological point of view, neurons begin dying within 5 min after the loss of oxygen supply [5]. Once ischemia
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