Protein phosphatase 2A activators reverse age-related behavioral changes by targeting neural cell senescence.
Protein phosphatase 2A activators reverse age-related behavioral changes by targeting neural cell senescence.
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作者：
在老年人中观察到的行为变化的细胞衰老的贡献仍然难以捉摸。在这里，我们观察到衰老与斑马鱼和小鼠大脑中蛋白磷酸酶2A（PP 2A）活性的下降有关。此外，激活PP 2A的药物逆转了与年龄相关的行为变化。我们开发了一种转基因斑马鱼模型，通过敲除PP 2A调控亚基ppp 2 r2 c基因来降低PP 2A在大脑中的活性。突变鱼表现出在老年动物中观察到的行为表型和神经细胞的过早积累，这些神经细胞对细胞衰老标记物呈阳性，包括衰老相关β-半乳糖苷酶、cdkn 2a/B、cdkn 1a水平升高、衰老相关分泌表型基因表达以及DNA损伤信号水平升高。行为和细胞衰老表型逆转突变鱼通过治疗衰老的ABT 263或不同的PP 2A激活剂，以及通过cdkn 1a或tp 53基因消融。在Ppp 2 r2 c下调的小鼠原代神经细胞中证明了PP 2A激活剂的Senomorphic功能。我们的结论是，PP 2A减少导致神经细胞衰老，从而导致与年龄相关的行为变化，PP 2A激活剂具有抗脑老化有害行为影响的衰老特性。在衰老过程中，蛋白磷酸酶2A（PP 2A）的活性在小鼠和斑马鱼的大脑中下降，导致神经细胞衰老和与年龄相关的行为变化。该过程可以通过PP 2A和senolytics的药理学活化剂逆转。
The contribution of cellular senescence to the behavioral changes observed in the elderly remains elusive. Here, we observed that aging is associated with a decline in protein phosphatase 2A (PP2A) activity in the brains of zebrafish and mice. Moreover, drugs activating PP2A reversed age‐related behavioral changes. We developed a transgenic zebrafish model to decrease PP2A activity in the brain through knockout of the ppp2r2c gene encoding a regulatory subunit of PP2A. Mutant fish exhibited the behavioral phenotype observed in old animals and premature accumulation of neural cells positive for markers of cellular senescence, including senescence‐associated β‐galactosidase, elevated levels cdkn2a/b, cdkn1a, senescence‐associated secretory phenotype gene expression, and an increased level of DNA damage signaling. The behavioral and cell senescence phenotypes were reversed in mutant fish through treatment with the senolytic ABT263 or diverse PP2A activators as well as through cdkn1a or tp53 gene ablation. Senomorphic function of PP2A activators was demonstrated in mouse primary neural cells with downregulated Ppp2r2c. We conclude that PP2A reduction leads to neural cell senescence thereby contributing to age‐related behavioral changes and that PP2A activators have senotherapeutic properties against deleterious behavioral effects of brain aging. During aging, the activity of the Protein Phosphatase 2A (PP2A) declines in the brain of mice and zebrafish, leading to neural cell senescence and aged‐related behavioral changes. This process can be reversed by pharmacological activators of PP2A and senolytics.
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凋亡启动和 ATM 信号传导的减弱赋予衰老造血干细胞响应 DNA 损伤的生存优势。
影响因子：
21.3
作者：
Gutierrez-Martinez P;Hogdal L;Nagai M;Kruta M;Singh R;Sarosiek K;Nussenzweig A;Beerman I;Letai A;Rossi DJ
通讯作者：
Rossi DJ
影响因子：
2.7
作者：
Egan, Rupert J.;Bergner, Carisa L.;Hart, Peter C.;Cachat, Jonathan M.;Canavello, Peter R.;Elegante, Marco F.;Elkhayat, Salem I.;Bartels, Brett K.;Tien, Anna K.;Tien, David H.;Mohnot, Sopan;Beeson, Esther;Glasgow, Eric;Amri, Hakima;Zukowska, Zofia;Kalueff, Allan V.
通讯作者：
Kalueff, Allan V.
影响因子：
6.1
作者：
Glorioso, Christin;Oh, Sunghee;Douillard, Gaelle Guilloux;Sibille, Etienne
通讯作者：
Sibille, Etienne
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
DOI：
10.15252/embj.201592862
发表时间：
2016-04-01
期刊：
The EMBO journal
影响因子：
--
作者：
Correia-Melo C;Marques FD;Anderson R;Hewitt G;Hewitt R;Cole J;Carroll BM;Miwa S;Birch J;Merz A;Rushton MD;Charles M;Jurk D;Tait SW;Czapiewski R;Greaves L;Nelson G;Bohlooly-Y M;Rodriguez-Cuenca S;Vidal-Puig A;Mann D;Saretzki G;Quarato G;Green DR;Adams PD;von Zglinicki T;Korolchuk VI;Passos JF
通讯作者：
Passos JF