Acylated Ghrelin is Protective Against 6-OHDA-induced Neurotoxicity by Regulating Autophagic Flux.
Acylated Ghrelin is Protective Against 6-OHDA-induced Neurotoxicity by Regulating Autophagic Flux.
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酰化 Ghrelin 通过调节自噬通量来预防 6-OHDA 诱导的神经毒性
DOI：
10.3389/fphar.2020.586302
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发表时间：
2020
影响因子：
5.6
通讯作者：
Guo Y
中科院分区：
文献类型：
--
作者：
He X;Yuan W;Liu F;Feng J;Guo Y
帕金森病（Parkinson's disease，PD）是最常见的神经退行性疾病之一，我们前期的研究发现自噬流功能障碍与6-OHDA诱导的PD模型中神经元死亡有关。酰化ghrelin是一种在中枢神经系统中具有多种作用的神经肽。本研究旨在探讨ghrelin在6-OHDA诱导的大鼠模型和SH-SY 5 Y细胞模型中是否具有神经保护作用，以及ghrelin是否与自噬流量调节有关。我们观察到ghrelin可以有效地减少阿扑吗啡诱导的6-OHDA诱导的PD大鼠的对侧旋转，保护酪氨酸羟化酶（TH）的表达，并增加细胞活力。上调自噬相关蛋白Atg 7和LC 3-II的表达，下调p62的表达，下调凋亡相关蛋白bax和切割型caspase 3的表达。腺病毒Ad-mCherry-GFP-LC 3B转染的SH-SY 5 Y细胞进一步显示ghrelin可以减轻6-OHDA诱导的自噬通量障碍。Lysotracker染色显示Ghrelin可逆转6-OHDA诱导的SH-SY 5 Y细胞溶酶体减少，免疫荧光染色显示TFEB水平逆转。用3-甲基腺嘌呤（3-MA）阻断Ghrelin和6-OHDA处理的大鼠自噬激活，对凋亡相关标志物无明显影响，而用氯喹阻断自噬体与溶酶体融合，可显著逆转Ghrelin下调bax/bcl-2比值和切割的caspase 3表达。此外，用siRNA敲除自噬上游调控因子ATG 7可进一步减少6-OHDA和ghrelin处理的SH-SY 5 Y细胞中的凋亡细胞数量，而用siRNA敲除溶酶体生物合成和功能的关键转录因子TFEB可完全消除ghrelin的抗凋亡作用。这些数据表明，ghrelin通过改善自噬通量功能障碍和恢复TFEB水平在6-OHDA诱导的PD模型中具有神经保护作用。
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, and our previous study revealed that autophagic flux dysfunction contributes to the neuron death in 6-OHDA-induced PD models. Acylated ghrelin is a neuropeptide that has a variety of actions in the central nervous system. In the current study, we aimed to investigate whether ghrelin is neuroprotective in 6-OHDA-induced rat model and SH-SY5Y cell model and whether it is related to autophagic flux regulation. We observed that ghrelin could effectively reduce apomorphine-induced contralateral rotation in 6-OHDA-induced PD rats, preserve the expression of tyrosine hydroxylase (TH) and increase the cell viability. It could upregulate the expression of autophagy related proteins like Atg7 and LC3-II and downregulate p62, and downregulate apoptosis related proteins like bax and cleaved caspase 3. SH-SY5Y cells transfected with adenovirus Ad-mCherry-GFP-LC3B further revealed that ghrelin could relieve the autophagic flux dysfunction induced by 6-OHDA. Lysotracker staining showed that ghrelin could reverse the decrease in lysosomes induced by 6-OHDA and immunofluorescence staining revealed a reverse of TFEB level in SH-SY5Y cells. Blocking autophagy activation with 3-methyladenine (3-MA) in rats treated with ghrelin and 6-OHDA showed no notable change in apoptosis-related markers, while blocking autophagosome fusion with lysosomes with chloroquine could notably reverse the downregulation of bax/bcl-2 ratio and cleaved caspase three expression by ghrelin. Additionally, knockdown ATG7, the upstream regulator of autophagy, with siRNA could further decrease the number of apoptotic cells in SH-SY5Y cells exposed to 6-OHDA and treated with ghrelin, while knockdown TFEB, a key transcription factor for lysosome biosynthesis and function, with siRNA could completely abolish the anti-apoptosis effect of ghrelin. These data suggest that ghrelin is neuroprotective in 6-OHDA-induced PD models via improving autophagic flux dysfunction and restoration of TFEB level.
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DOI：
10.1042/bcj20160498
发表时间：
2017-04-13
期刊：
The Biochemical journal
影响因子：
--
作者：
Walden H;Muqit MM
通讯作者：
Muqit MM
DOI：
10.1523/jneurosci.3890-09.2009
发表时间：
2009-11-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Andrews ZB;Erion D;Beiler R;Liu ZW;Abizaid A;Zigman J;Elsworth JD;Savitt JM;DiMarchi R;Tschoep M;Roth RH;Gao XB;Horvath TL
通讯作者：
Horvath TL
影响因子：
5.1
作者：
Haavik, Jan;Toska, Karen
通讯作者：
Toska, Karen
影响因子：
3.1
作者：
Dong, Juanjuan;Song, Ning;Jiang, Hong
通讯作者：
Jiang, Hong
DOI：
10.1056/nejmoa0901281
发表时间：
2009-10-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Sidransky E;Nalls MA;Aasly JO;Aharon-Peretz J;Annesi G;Barbosa ER;Bar-Shira A;Berg D;Bras J;Brice A;Chen CM;Clark LN;Condroyer C;De Marco EV;Dürr A;Eblan MJ;Fahn S;Farrer MJ;Fung HC;Gan-Or Z;Gasser T;Gershoni-Baruch R;Giladi N;Griffith A;Gurevich T;Januario C;Kropp P;Lang AE;Lee-Chen GJ;Lesage S;Marder K;Mata IF;Mirelman A;Mitsui J;Mizuta I;Nicoletti G;Oliveira C;Ottman R;Orr-Urtreger A;Pereira LV;Quattrone A;Rogaeva E;Rolfs A;Rosenbaum H;Rozenberg R;Samii A;Samaddar T;Schulte C;Sharma M;Singleton A;Spitz M;Tan EK;Tayebi N;Toda T;Troiano AR;Tsuji S;Wittstock M;Wolfsberg TG;Wu YR;Zabetian CP;Zhao Y;Ziegler SG
通讯作者：
Ziegler SG