TY - JOUR
T1 - Circular RNA TLK1 aggravates neuronal injury and neurological deficits after ischemic stroke via miR-335-3p/TIPARP
AU - Wu, Fangfang
AU - Han, Bing
AU - Wu, Shusheng
AU - Yang, Li
AU - Leng, Shuo
AU - Li, Mingyue
AU - Liao, Jiefeng
AU - Wang, Guangtian
AU - Ye, Qingqing
AU - Zhang, Yuan
AU - Chen, Haifeng
AU - Chen, Xufeng
AU - Zhong, Ming
AU - Xu, Yun
AU - Liu, Qiang
AU - Zhang, John H.
AU - Yao, Honghong
N1 - Publisher Copyright:
Copyright © 2019 the authors
PY - 2019/9/11
Y1 - 2019/9/11
N2 - Circular RNAs (circRNAs) are expressed at high levels in the brain and are involved in various CNS diseases. However, the potential role of circRNAs in ischemic stroke-associated neuronal injury remains largely unknown. Here, we investigated the important functions of circRNA
TLK1 (circTLK1) in this process. The levels of circTLK1 were significantly increased in brain tissues in a mouse model of focal cerebral ischemia and reperfusion. Knockdown of circTLK1 significantly decreased infarct volumes, attenuated neuronal injury, and improved neurological deficits. Furthermore, circTLK1 functioned as an endogenous miR-335-3p sponge to inhibit miR-335-3p activity, resulting in the increase of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible poly (ADP-ribose) polymerase expression and a subsequent exacerbation of neuronal injury. Clinical studies confirmed increased levels of circTLK1 in the plasma of patients with acute ischemic stroke (59 males and 12 females). Our findings reveal a detrimental role of circTLK1 in ischemic brain injury.
SIGNIFICANCE STATEMENT The extent of neuronal injury after brain ischemia is a primary factor determining stroke outcomes. However, the molecular switches that control the death of ischemic neurons are poorly understood. While our previous studies indicated the involvement of circRNAs in ischemic stroke, the potential role of circRNAs in neuronal injury remains largely unknown. The levels of circTLK1 were significantly increased in the brain tissue and plasma isolated from animal models of ischemic stroke and patients. Knockdown of circTLK1 significantly decreased infarct volumes, attenuated neuronal injury, and improved subsequent long-term neurological deficits. To our knowledge, these results provide the first definitive evidence that circTLK1 is detrimental in ischemic stroke.
AB - Circular RNAs (circRNAs) are expressed at high levels in the brain and are involved in various CNS diseases. However, the potential role of circRNAs in ischemic stroke-associated neuronal injury remains largely unknown. Here, we investigated the important functions of circRNA
TLK1 (circTLK1) in this process. The levels of circTLK1 were significantly increased in brain tissues in a mouse model of focal cerebral ischemia and reperfusion. Knockdown of circTLK1 significantly decreased infarct volumes, attenuated neuronal injury, and improved neurological deficits. Furthermore, circTLK1 functioned as an endogenous miR-335-3p sponge to inhibit miR-335-3p activity, resulting in the increase of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible poly (ADP-ribose) polymerase expression and a subsequent exacerbation of neuronal injury. Clinical studies confirmed increased levels of circTLK1 in the plasma of patients with acute ischemic stroke (59 males and 12 females). Our findings reveal a detrimental role of circTLK1 in ischemic brain injury.
SIGNIFICANCE STATEMENT The extent of neuronal injury after brain ischemia is a primary factor determining stroke outcomes. However, the molecular switches that control the death of ischemic neurons are poorly understood. While our previous studies indicated the involvement of circRNAs in ischemic stroke, the potential role of circRNAs in neuronal injury remains largely unknown. The levels of circTLK1 were significantly increased in the brain tissue and plasma isolated from animal models of ischemic stroke and patients. Knockdown of circTLK1 significantly decreased infarct volumes, attenuated neuronal injury, and improved subsequent long-term neurological deficits. To our knowledge, these results provide the first definitive evidence that circTLK1 is detrimental in ischemic stroke.
KW - Circular RNA TLK1
KW - MiR-335
KW - Neuronal injury
KW - Stroke
KW - TIPARP
KW - Gene Knockdown Techniques/methods
KW - MicroRNAs/genetics
KW - Humans
KW - Mice, Inbred C57BL
KW - Middle Aged
KW - Stroke/diagnostic imaging
KW - Male
KW - Animals
KW - Neurons/metabolism
KW - Nucleoside Transport Proteins
KW - Female
KW - Aged
KW - Mice
KW - Brain Ischemia/diagnostic imaging
KW - Poly(ADP-ribose) Polymerases/genetics
KW - RNA, Circular/antagonists & inhibitors
KW - Protein Serine-Threonine Kinases/antagonists & inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85072133009&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072133009&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0299-19.2019
DO - 10.1523/JNEUROSCI.0299-19.2019
M3 - Article
C2 - 31311824
SN - 0270-6474
VL - 39
SP - 7369
EP - 7393
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 37
ER -