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

R. Anne Stetler, Yanqin Gao, Rehana K. Leak, Zhongfang Weng, Yejie Shi, Lili Zhang, Hongjian Pu, Feng Zhang, Xiaoming Hu, Sulaiman Hassan, Carolyn Ferguson, Gregg E. Homanics, Guodong Cao, Michael V. L. Bennett, Jun Chen

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E3558-E3567
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number25
DOIs
StatePublished - Jun 21 2016

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DNA-(Apurinic or Apyrimidinic Site) Lyase
Transcription Factor AP-1
Oxidation-Reduction
Stroke
Wounds and Injuries
Transient Ischemic Attack
DNA Damage
Gray Matter
White Matter
Endonucleases
Oligodendroglia
Demyelinating Diseases
Tamoxifen
Myelin Sheath
Knockout Mice
DNA Repair
Infarction
Oxidative Stress
Central Nervous System
Communication

Keywords

  • Base excision repair
  • Ischemia
  • Neurodegeneration
  • Oxidative DNA damage
  • White matter injury

ASJC Scopus subject areas

  • General

Cite this

APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury. / Stetler, R. Anne; Gao, Yanqin; Leak, Rehana K.; Weng, Zhongfang; Shi, Yejie; Zhang, Lili; Pu, Hongjian; Zhang, Feng; Hu, Xiaoming; Hassan, Sulaiman; Ferguson, Carolyn; Homanics, Gregg E.; Cao, Guodong; Bennett, Michael V. L.; Chen, Jun.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 25, 21.06.2016, p. E3558-E3567.

Research output: Contribution to journalArticle

Stetler, RA, Gao, Y, Leak, RK, Weng, Z, Shi, Y, Zhang, L, Pu, H, Zhang, F, Hu, X, Hassan, S, Ferguson, C, Homanics, GE, Cao, G, Bennett, MVL & Chen, J 2016, 'APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 25, pp. E3558-E3567. https://doi.org/10.1073/pnas.1606226113
Stetler, R. Anne ; Gao, Yanqin ; Leak, Rehana K. ; Weng, Zhongfang ; Shi, Yejie ; Zhang, Lili ; Pu, Hongjian ; Zhang, Feng ; Hu, Xiaoming ; Hassan, Sulaiman ; Ferguson, Carolyn ; Homanics, Gregg E. ; Cao, Guodong ; Bennett, Michael V. L. ; Chen, Jun. / APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 25. pp. E3558-E3567.
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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.",
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AU - Stetler, R. Anne

AU - Gao, Yanqin

AU - Leak, Rehana K.

AU - Weng, Zhongfang

AU - Shi, Yejie

AU - Zhang, Lili

AU - Pu, Hongjian

AU - Zhang, Feng

AU - Hu, Xiaoming

AU - Hassan, Sulaiman

AU - Ferguson, Carolyn

AU - Homanics, Gregg E.

AU - Cao, Guodong

AU - Bennett, Michael V. L.

AU - Chen, Jun

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N2 - 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.

AB - 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.

KW - Base excision repair

KW - Ischemia

KW - Neurodegeneration

KW - Oxidative DNA damage

KW - White matter injury

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