Extracellular poly(ADP-ribose) is a neurotrophic signal that upregulates glial cell line-derived neurotrophic factor (GDNF) levels in vitro and in vivo.
Extracellular poly(ADP-ribose) is a neurotrophic signal that upregulates glial cell line-derived neurotrophic factor (GDNF) levels in vitro and in vivo.
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细胞外聚（ADP-核糖）是一种神经营养信号，可在体外和体内上调神经胶质细胞系源性神经营养因子（GDNF）水平。
DOI：
10.1016/j.bbrc.2017.01.129
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Takeuchi T.
中科院分区：
文献类型：
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作者：
Nakajima H;Itakura M;Sato K;Nakamura S;Azuma YT;Takeuchi T.
神经元中聚腺苷二磷酸核糖（PAR）聚合酶-1（PARP-1）催化PAR的合成。PARP 1在神经退行性疾病的各种类型的脑损伤中发挥作用。在神经元中，氧化应激过程中PARP-1的过度活化诱导了强大的PAR形成，这消耗了烟酰胺腺嘌呤二核苷酸水平并导致细胞死亡。然而，新形成的PAR在神经退行性疾病中的作用仍然难以捉摸。我们假设PAR的作用可能发生在受损神经元泄漏后的细胞外空间。在此，我们报道了细胞外PAR（EC-PAR）作为一种神经保护分子，在体外和体内通过诱导星形胶质细胞合成胶质细胞源性神经营养因子（GDNF）来诱导神经元细胞死亡。在原代大鼠星形胶质细胞中，外源性EC-PAR处理产生GDNF，但不产生其他神经营养因子。该效应具有浓度依赖性，并且不影响大鼠C6星形细胞瘤细胞的细胞活力。局部注射EC-PAR到大鼠纹状体上调活化星形胶质细胞GDNF水平，并改善帕金森病大鼠单侧6-羟基多巴胺模型的致病旋转行为。这些发现表明，EC-PAR作为一种神经营养增强剂，通过上调GDNF水平。这种作用保护了氧化应激诱导的脑损伤后剩余的神经元，例如帕金森病。
Synthesis of poly(ADP-ribose) (PAR) is catalyzed by PAR polymerase-1 (PARP-1) in neurons. PARP1 plays a role in various types of brain damage in neurodegenerative disorders. In neurons, overactivation of PARP-1 during oxidative stress induces robust PAR formation, which depletes nicotinamide adenine dinucleotide levels and leads to cell death. However, the role of the newly-formed PAR in neurodegenerative disorders remains elusive. We hypothesized that the effects of PAR could occur in the extracellular space after it is leaked from damaged neurons. Here we report that extracellular PAR (EC-PAR) functions as a neuroprotective molecule by inducing the synthesis of glial cell line-derived neurotrophic factor (GDNF) in astrocytes during neuronal cell death, bothin vitroandin vivo. In primary rat astrocytes, exogenous treatment with EC-PAR produced GDNF but not other neurotrophic factors. The effect was concentration-dependent and did not affect cell viability in rat C6 astrocytoma cells. Topical injection of EC-PAR into rat striatum upregulated GDNF levels in activated astrocytes and improved pathogenic rotation behavior in a unilateral 6-hydroxydopamine model of Parkinson disease in rats. These findings indicate that EC-PAR acts as a neurotrophic enhancer by upregulating GDNF levels. This effect protects the remaining neurons following oxidative stress-induced brain damage, such as that seen with Parkinson disease.