APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury

DOI

10.1073/pnas.1606226113

R Anne Stetler, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Yanqin Gao, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213;
Rehana K. Leak, Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282;
Zhongfang Weng, Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Yejie Shi, Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Lili Zhang, Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Hongjian Pu, Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213;
Feng Zhang, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Xiaoming Hu, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Sulaiman Hassan, Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Carolyn Ferguson, Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261;
Gregg E. Homanics, Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261;
Guodong Cao, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Michael V. Bennett, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461 michael.bennett@einstein.yu.edu chenj2@upmc.edu.
Jun Chen, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261; michael.bennett@einstein.yu.edu chenj2@upmc.edu.

Document Type

Journal Article

Publication Date

6-21-2016

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

113

Issue

25

First Page

E3558

Last Page

67

Keywords

base excision repair, ischemia, neurodegeneration, oxidative DNA damage, white matter injury

Abstract

A major hallmark of oxidative DNA damage after stroke is the induction of apurinic/apyrimidinic (AP) sites and strand breaks. To mitigate cell loss after oxidative DNA damage, ischemic cells rapidly engage the base excision-repair proteins, such as the AP site-repairing enzyme AP endonuclease-1 (APE1), also named redox effector factor-1 (Ref-1). Although forced overexpression of APE1 is known to protect against oxidative stress-induced neurodegeneration, there is no concrete evidence demonstrating a role for endogenous APE1 in the long-term recovery of gray and white matter following ischemic injury. To address this gap, we generated, to our knowledge, the first APE1 conditional knockout (cKO) mouse line under control of tamoxifen-dependent Cre recombinase. Using a well-established model of transient focal cerebral ischemia (tFCI), we show that induced deletion of APE1 dramatically enlarged infarct volume and impaired the recovery of sensorimotor and cognitive deficits. APE1 cKO markedly increased postischemic neuronal and oligodendrocyte degeneration, demonstrating that endogenous APE1 preserves both gray and white matter after tFCI. Because white matter repair is instrumental in behavioral recovery after stroke, we also examined the impact of APE1 cKO on demyelination and axonal conduction and discovered that APE1 cKO aggravated myelin loss and impaired neuronal communication following tFCI. Furthermore, APE1 cKO increased AP sites and activated the prodeath signaling proteins, PUMA and PARP1, after tFCI in topographically distinct manners. Our findings provide evidence that endogenous APE1 protects against ischemic infarction in both gray and white matter and facilitates the functional recovery of the central nervous system after mild stroke injury.

Open Access

OA

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