Guanabenz promotes neuronal survival via enhancement of ATF4 and parkin expression in models of Parkinson disease.
Guanabenz promotes neuronal survival via enhancement of ATF4 and parkin expression in models of Parkinson disease.
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DOI：
10.1016/j.expneurol.2018.01.015
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发表时间：
2018-05
影响因子：
5.3
通讯作者：
Levy OA
中科院分区：
文献类型：
--
作者：
Sun X;Aimé P;Dai D;Ramalingam N;Crary JF;Burke RE;Greene LA;Levy OA
帕金森病（Parkinson disease，PD）的主要致病因素是Parkin功能下降。增加parkin水平提高PD相关神经元死亡模型的存活率，是一个有前途的治疗目标。以前，我们证明了转录因子ATF 4通过维持parkin水平来促进对PD模拟应激的反应。ATF 4翻译通过翻译起始因子eIF 2 α的磷酸化上调。小分子胍那苄通过阻断GADD 34（一种促进eIF 2 α去磷酸化的调节蛋白）的功能来增强eIF 2 α磷酸化。我们检验了以下假设：胍那苄通过抑制GADD 34，从而增加eIF 2 α磷酸化和升高ATF 4，将通过上调parkin来改善PD模型的存活率。我们发现GADD 34被6-OHDA强烈诱导，并且GADD 34在PD病例中在多巴胺能黑质神经元中的定位显著改变。我们进一步证明，胍那苄减弱6-羟基多巴胺（6-OHDA）诱导的细胞死亡分化的PC 12细胞和原腹侧中脑多巴胺能神经元的文化，和多巴胺能神经元在黑质的小鼠。在培养模型中，胍那苄还可增加eIF 2 α磷酸化和ATF 4和parkin水平，以响应6-OHDA。此外，如果ATF 4或parkin被沉默，则胍那苄的保护作用丧失。我们还发现了类似的结果，在一个不同的模型的神经元死亡：原代培养的皮质神经元处理的拓扑异构酶I抑制剂喜树碱，其中胍那苄限制喜树碱诱导的神经元死亡的ATF 4和帕金森氏症依赖的方式。总之，我们的数据表明，胍那苄和其他GADD 34抑制剂可用作治疗剂，以提高parkin水平，从而减缓PD和其他神经退行性疾病中的神经退行性病变。
Reduced function of parkin appears to be a central pathogenic event in Parkinson disease (PD). Increasing parkin levels enhances survival in models of PD-related neuronal death and is a promising therapeutic objective. Previously, we demonstrated that the transcription factor ATF4 promotes survival in response to PD-mimetic stressors by maintaining parkin levels. ATF4 translation is up-regulated by phosphorylation of the translation initiation factor eIF2α. The small molecule guanabenz enhances eIF2α phosphorylation by blocking the function of GADD34, a regulatory protein that promotes eIF2α dephosphorylation. We tested the hypothesis that guanabenz, by inhibiting GADD34 and consequently increasing eIF2α phosphorylation and elevating ATF4, would improve survival in models of PD by up-regulating parkin. We found that GADD34 is strongly induced by 6-OHDA, and that GADD34 localization is dramatically altered in dopaminergic substantia nigra neurons in PD cases. We further demonstrated that guanabenz attenuates 6-hydroxydopamine (6-OHDA) induced cell death of differentiated PC12 cells and primary ventral midbrain dopaminergic neurons in culture, and of dopaminergic neurons in the substantia nigra of mice. In culture models, guanabenz also increases eIF2α phosphorylation and ATF4 and parkin levels in response to 6-OHDA. Furthermore, if either ATF4 or parkin is silenced, then the protective effect of guanabenz is lost. We also found similar results in a distinct model of neuronal death: primary cultures of cortical neurons treated with the topoisomerase I inhibitor camptothecin, in which guanabenz limited camptothecin-induced neuronal death in an ATF4- and parkin-dependent manner. In summary, our data suggest that guanabenz and other GADD34 inhibitors could be used as therapeutic agents to boost parkin levels and thereby slow neurodegeneration in PD and other neurodegenerative conditions.
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影响因子：
5.3
作者：
Liu J;Pasini S;Shelanski ML;Greene LA
通讯作者：
Greene LA
影响因子：
64.8
作者：
Moreno, Julie A.;Radford, Helois;Peretti, Diego;Steinert, Joern R.;Verity, Nicholas;Martin, Maria Guerra;Halliday, Mark;Morgan, Jason;Dinsdale, David;Ortori, Catherine A.;Barrett, David A.;Tsaytler, Pavel;Bertolotti, Anne;Willis, Anne E.;Bushell, Martin;Mallucci, Giovanna R.
通讯作者：
Mallucci, Giovanna R.
DOI：
10.1126/science.aaa4484
发表时间：
2015-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Das I;Krzyzosiak A;Schneider K;Wrabetz L;D'Antonio M;Barry N;Sigurdardottir A;Bertolotti A
通讯作者：
Bertolotti A
影响因子：
5.3
作者：
Galehdar, Zohreh;Swan, Patrick;Cregan, Sean P.
通讯作者：
Cregan, Sean P.
影响因子：
5
作者：
Phu Hai Nguyen;Hammoud, Hassan;Voisset, Cecile
通讯作者：
Voisset, Cecile