CK2 inhibition confers functional protection to young and aging axons against ischemia by differentially regulating the CDK5 and AKT signaling pathways.
CK2 inhibition confers functional protection to young and aging axons against ischemia by differentially regulating the CDK5 and AKT signaling pathways.
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DOI：
10.1016/j.nbd.2018.05.011
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发表时间：
2019-06
影响因子：
6.1
通讯作者：
Brunet, Sylvain
中科院分区：
文献类型：
--
作者：
Bastian, Chinthasagar;Quinn, John;Tripathi, Ajai;Aquila, Danielle;McCray, Andrew;Dutta, Ranjan;Baltan, Selva;Brunet, Sylvain
白色物质（WM）在大多数中风中受损，这有助于恢复期间的功能缺陷。酪蛋白激酶2（CK 2）是一种在脑（包括WM）中表达的蛋白激酶。为了评估CK 2抑制对氧葡萄糖剥夺（OGD）后轴突恢复的影响，在有或没有选择性CK 2抑制剂CX-4945的情况下使小鼠视神经（MON）（其为纯WM束）经受OGD。CX-4945应用在OGD期间保留轴突功能，并且当在OGD之前或之后应用时促进轴突功能恢复。CK 2抑制的这种保护作用与少突胶质细胞的保存和轴突结构和轴突线粒体的保护有关。为了研究相关的下游信号通路，靶向CK 2 α亚基的siRNA将CDK 5和AKT鉴定为下游分子。因此，MK-2206和roscovitine（分别为选择性AKT和CDK 5抑制剂）仅在OGD前应用时才能保护年轻和衰老WM功能。然而，一种新的泛AKT变构抑制剂ARQ-092，其靶向AKT的非活性和活性构象，当在OGD之前或之后应用时，对年轻和老化的轴突提供保护。这些结果表明，AKT和CDK 5信号通路有助于缺血期间CK 2抑制所赋予的WM功能保护，而抑制激活的AKT信号通路在不依赖于年龄的WM中CK 2抑制所赋予的缺血后保护中起主要作用。CK 2抑制剂目前正用于癌症患者的临床试验;因此，我们的研究结果将为通过添加新的靶点将这些药物重新用作中风患者的治疗选择提供理论依据。
White matter (WM) is injured in most strokes, which contributes to functional deficits during recovery. Casein kinase 2 (CK2) is a protein kinase that is expressed in brain, including WM. To assess the impact of CK2 inhibition on axon recovery following oxygen glucose deprivation (OGD), mouse optic nerves (MONs), which are pure WM tracts, were subjected to OGD with or without the selective CK2 inhibitor CX-4945. CX-4945 application preserved axon function during OGD and promoted axon function recovery when applied before or after OGD. This protective effect of CK2 inhibition correlated with preservation of oligodendrocytes and conservation of axon structure and axonal mitochondria. To investigate the pertinent downstream signaling pathways, siRNA targeting the CK2α subunit identified CDK5 and AKT as downstream molecules. Consequently, MK-2206 and roscovitine, which are selective AKT and CDK5 inhibitors, respectively, protected young and aging WM function only when applied before OGD. However, a novel pan-AKT allosteric inhibitor, ARQ-092, which targets both the inactive and active conformations of AKT, conferred protection to young and aging axons when applied before or after OGD. These results suggest that AKT and CDK5 signaling contribute to the WM functional protection conferred by CK2 inhibition during ischemia, while inhibition of activated AKT signaling plays the primary role in post-ischemic protection conferred by CK2 inhibition in WM independent of age. CK2 inhibitors are currently being used in clinical trials for cancer patients; therefore, our results will provide rationale for repurposing these drugs as therapeutic options for stroke patients by adding novel targets.
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影响因子：
5
作者：
Brunet S;Emrick MA;Sadilek M;Scheuer T;Catterall WA
通讯作者：
Catterall WA
DOI：
10.1083/jcb.200805169
发表时间：
2008-12-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bréchet A;Fache MP;Brachet A;Ferracci G;Baude A;Irondelle M;Pereira S;Leterrier C;Dargent B
通讯作者：
Dargent B
影响因子：
4.7
作者：
Baltan S
通讯作者：
Baltan S
影响因子：
5.6
作者：
Baltan, Selva
通讯作者：
Baltan, Selva
影响因子：
12.4
作者：
Di Maira, G;Salvi, M;Ruzzene, M
通讯作者：
Ruzzene, M