The drug adaptaquin blocks ATF4/CHOP-dependent pro-death Trib3 induction and protects in cellular and mouse models of Parkinson's disease.
The drug adaptaquin blocks ATF4/CHOP-dependent pro-death Trib3 induction and protects in cellular and mouse models of Parkinson's disease.
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DOI：
10.1016/j.nbd.2019.104725
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发表时间：
2020-03
影响因子：
6.1
通讯作者：
Greene LA
中科院分区：
文献类型：
--
作者：
Aimé P;Karuppagounder SS;Rao A;Chen Y;Burke RE;Ratan RR;Greene LA
确定帕金森病 (PD) 的致病途径和针对这些途径的药物仍然具有挑战性。我们发现了一条与 PD 相关的通路，其中应激调节的异二聚体转录复合物 CHOP/ATF4 诱导神经元死亡蛋白 Trib3，进而耗尽神经元存活蛋白 Parkin。在这里，我们试图确定抑制 ATF4 依赖性转录的药物 Adaptaquin 是否可以抑制 PD 细胞和动物模型中 Trib3 的诱导和神经元死亡。在体外评估神经元 PC12 细胞和腹侧中脑多巴胺能神经元在暴露于 6-羟基多巴胺或 1-甲基-4-苯基吡啶鎓（有或没有 Adaptaquin 联合治疗）后的存活率、转录因子水平和 Trib3 或 Parkin 表达。将 6-羟基多巴胺注射到内侧前脑束中，用于检查全身适应剂对信号传导、黑质多巴胺能神经元存活和纹状体投射以及运动行为的影响。在培养物和动物模型中，adaptaquin 抑制了 ATF4 和/或 CHOP 的升高以及对 1-methyl-4-苯基吡啶鎓和/或 6-羟基多巴胺的反应的 Trib3 的诱导。在培养中，adaptaquin 保留了 Parkin 水平，提供了神经保护并保留了形态。在小鼠模型中，adaptaquin 治疗增强了多巴胺能神经元的存活率，并显着保护了它们的纹状体投射。它还显着增强了黑质纹状体功能的保留。这些发现定义了一种新的药理学方法，涉及药物 Adaptaquin（一种低氧适应的选择性调节剂），用于抑制 PD 毒素模型中的 Parkin 丢失和神经变性。由于 Adaptaquin 具有已知对人类安全的羟喹啉主链，这些发现为推进其在帕金森病的临床评估提供了坚实的理由。
Identifying disease-causing pathways and drugs that target them in Parkinson’s disease (PD) has remained challenging. We uncovered a PD-relevant pathway in which the stress-regulated heterodimeric transcription complex CHOP/ATF4 induces the neuron prodeath protein Trib3 that in turn depletes the neuronal survival protein Parkin. Here we sought to determine whether the drug adaptaquin, which inhibits ATF4-dependent transcription, could suppress Trib3 induction and neuronal death in cellular and animal models of PD. Neuronal PC12 cells and ventral midbrain dopaminergic neurons were assessed in vitro for survival, transcription factor levels and Trib3 or Parkin expression after exposure to 6-hydroxydopamine or 1-methyl-4-phenylpyridinium with or without adaptaquin co-treatment. 6-hydroxydopamine injection into the medial forebrain bundle was used to examine the effects of systemic adaptaquin on signaling, substantia nigra dopaminergic neuron survival and striatal projections as well as motor behavior. In both culture and animal models, adaptaquin suppressed elevation of ATF4 and/or CHOP and induction of Trib3 in response to 1-methyl-4-phenylpyridinium and/or 6-hydroxydopamine. In culture, adaptaquin preserved Parkin levels, provided neuroprotection and preserved morphology. In the mouse model, adaptaquin treatment enhanced survival of dopaminergic neurons and substantially protected their striatal projections. It also significantly enhanced retention of nigrostriatal function. These findings define a novel pharmacological approach involving the drug adaptaquin, a selective modulator of hypoxic adaptation, for suppressing Parkin loss and neurodegeneration in toxin models of PD. As adaptaquin possesses an oxyquinoline backbone with known safety in humans, these findings provide a firm rationale for advancing it towards clinical evaluation in PD.
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影响因子：
3.4
作者：
Kühn, K;Wellen, J;Stichel, CC
通讯作者：
Stichel, CC
影响因子：
17.1
作者：
Karuppagounder SS;Alim I;Khim SJ;Bourassa MW;Sleiman SF;John R;Thinnes CC;Yeh TL;Demetriades M;Neitemeier S;Cruz D;Gazaryan I;Killilea DW;Morgenstern L;Xi G;Keep RF;Schallert T;Tappero RV;Zhong J;Cho S;Maxfield FR;Holman TR;Culmsee C;Fong GH;Su Y;Ming GL;Song H;Cave JW;Schofield CJ;Colbourne F;Coppola G;Ratan RR
通讯作者：
Ratan RR
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
50.3
作者：
Lee, S;Nakamura, E;Schlisio, S
通讯作者：
Schlisio, S
影响因子：
8.6
作者：
Dawson, Ted M.;Dawson, Valina L.
通讯作者：
Dawson, Valina L.