激活转录因子4的上调在帕金森病大鼠模型中诱导黑质多巴胺能神经元严重缺失。
Up-regulation of activating transcription factor 4 induces severe loss of dopamine nigral neurons in a rat model of Parkinson's disease.
作者信息
Gully Joseph C, Sergeyev Valeriy G, Bhootada Yogesh, Mendez-Gomez Hector, Meyers Craig A, Zolotukhin Sergey, Gorbatyuk Marina S, Gorbatyuk Oleg S
机构信息
Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Biology, Udmurt State University, Izhevsk, Russia.
出版信息
Neurosci Lett. 2016 Aug 3;627:36-41. doi: 10.1016/j.neulet.2016.05.039. Epub 2016 May 24.
Activating transcription factor 4 (ATF4) is a member of the PERK signaling pathway, which directly binds endoplasmic reticulum stress target genes and plays a crucial role in both adaptations to stress and activation of apoptosis. Previous publications demonstrated conflicting evidence on the role of ATF4 in the pathogenesis of neurodegenerative disorders. In this study, we used recombinant adeno-associate virus (rAAV)-mediated gene transfer to investigate if the sustained up-regulation of ATF4 launches a pro-survival or pro-death trend in the dopamine (DA) cells of the substantia nigra pars compacta in a rat model of Parkinson-like neurodegeneration induced by human alpha-synuclein (αS) overexpression. We showed that ATF4 does not protect nigral DA neurons against an αS-induced pathology. Moreover, the rAAV-mediated overexpression of ATF4 resulted in severe nigra-striatal degeneration via activation of caspases 3/7.
激活转录因子4（ATF4）是PERK信号通路的成员，它直接结合内质网应激靶基因，在应激适应和细胞凋亡激活中都起着关键作用。先前的出版物关于ATF4在神经退行性疾病发病机制中的作用提供了相互矛盾的证据。在本研究中，我们使用重组腺相关病毒（rAAV）介导的基因转移来研究在人α-突触核蛋白（αS）过表达诱导的帕金森样神经退行性变大鼠模型中，ATF4的持续上调是否会在黑质致密部的多巴胺（DA）细胞中引发促生存或促死亡趋势。我们发现ATF4不能保护黑质DA神经元免受αS诱导的病理损伤。此外，rAAV介导的ATF4过表达通过激活半胱天冬酶3/7导致严重的黑质-纹状体变性。
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