BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1.
BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1.
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DOI：
10.1007/s12017-013-8270-x
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发表时间：
2014-03
影响因子：
3.5
通讯作者：
Mattson, Mark P.
中科院分区：
文献类型：
--
作者：
Yang, Jenq-Lin;Lin, Yu-Ting;Chuang, Pei-Chin;Bohr, Vilhelm A.;Mattson, Mark P.
关键词：
脑源性神经营养因子（BDNF）在脑发育过程中促进神经元的存活和生长，并介导活动依赖性突触可塑性和相关的学习和记忆。BDNF水平在阿尔茨海默病、帕金森病和亨廷顿病中受影响的脑区域中降低，并且BDNF水平的升高可以改善这些疾病的实验模型中的神经元功能障碍和变性。由于神经元在正常活动和神经退行性疾病中在其DNA中积累氧化损伤，我们确定BDNF是否以及如何影响神经元科普氧化DNA损伤的能力。我们发现，BDNF保护大脑皮层神经元免受氧化DNA损伤诱导的死亡的机制，涉及增强DNA修复。BDNF通过激活环AMP反应元件结合蛋白（CREB）刺激DNA修复，CREB反过来诱导脱嘌呤/脱嘧啶核酸内切酶1（APE 1）的表达，APE 1是碱基切除DNA修复途径中的关键酶。通过RNA干扰抑制APE 1或TrkB，可以消除BDNF保护神经元免受氧化DNA损伤诱导的死亡的能力。BDNF激活CREB和上调APE 1表达的能力被TrkB的shRNA以及TrkB、PI 3激酶和Akt激酶的抑制剂所消除。自愿跑轮运动显著增加BDNF水平，激活CREB，并上调小鼠大脑皮层和海马中的APE 1，这表明运动可能保护神经元免受氧化DNA损伤的新机制。我们的发现揭示了BDNF通过诱导DNA修复酶APE 1的表达来增强DNA修复的先前未知的能力。
Brain-derived neurotrophic factor (BDNF) promotes the survival and growth of neurons during brain development and mediates activity-dependent synaptic plasticity and associated learning and memory in the adult. BDNF levels are reduced in brain regions affected in Alzheimer’s, Parkinson’s, and Huntington’s diseases, and elevation of BDNF levels can ameliorate neuronal dysfunction and degeneration in experimental models of these diseases. Because neurons accumulate oxidative lesions in their DNA during normal activity and in neurodegenerative disorders, we determined whether and how BDNF affects the ability of neurons to cope with oxidative DNA damage. We found that BDNF protects cerebral cortical neurons against oxidative DNA damage-induced death by a mechanism involving enhanced DNA repair. BDNF stimulates DNA repair by activating cyclic AMP response element-binding protein (CREB), which, in turn, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair pathway. Suppression of either APE1 or TrkB by RNA interference abolishes the ability of BDNF to protect neurons against oxidized DNA damage-induced death. The ability of BDNF to activate CREB and upregulate APE1 expression is abolished by shRNA of TrkB as well as inhibitors of TrkB, PI3 kinase, and Akt kinase. Voluntary running wheel exercise significantly increases levels of BDNF, activates CREB, and upregulates APE1 in the cerebral cortex and hippocampus of mice, suggesting a novel mechanism whereby exercise may protect neurons from oxidative DNA damage. Our findings reveal a previously unknown ability of BDNF to enhance DNA repair by inducing the expression of the DNA repair enzyme APE1.
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影响因子：
21.3
作者：
Huang, En;Qu, Dianbo;Park, David S.
通讯作者：
Park, David S.
影响因子：
14.9
作者：
Kulkarni, Avanti;McNeill, Daniel R.;Wilson, David M., III
通讯作者：
Wilson, David M., III
影响因子：
6.3
作者：
Liu, Dong;Croteau, Deborah L.;Mattson, Mark P.
通讯作者：
Mattson, Mark P.
DOI：
10.1523/jneurosci.2135-08.2008
发表时间：
2008-10-29
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kharebava G;Makonchuk D;Kalita KB;Zheng JJ;Hetman M
通讯作者：
Hetman M
影响因子：
2.9
作者：
Neeper, SA;GomezPinilla, F;Cotman, CW
通讯作者：
Cotman, CW