PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease.
PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease.
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DOI：
10.1016/j.neurobiolaging.2014.04.031
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发表时间：
2014-10
影响因子：
4.2
通讯作者：
Ohno M
中科院分区：
文献类型：
--
作者：
Devi L;Ohno M
越来越多的证据表明，真核起始因子-2α (eIF2α)的异常磷酸化可能通过持续的翻译抑制全球蛋白质合成来诱导突触衰竭和神经变性。然而，磷酸化eif2 α的升高也会引起mrna亚群的翻译激活，如β分泌酶BACE1和CREB抑制因子ATF4。因此，我们在5XFAD小鼠模型中测试了eIF2α激酶PERK的遗传减少是否可以预防这些有害事件并减轻阿尔茨海默病（AD）样神经病理和认知障碍。在5XFAD小鼠中，PERK单倍体功能不全阻断了PERK-eIF2α通路的过度激活，这可以通过PERK和eIF2α磷酸化的显著降低来证明。在AD模型中，PERK单倍不足足以挽救记忆缺陷和胆碱能神经变性。值得注意的是，PERK单倍体功能不全也阻止了BACE1的升高，导致5XFAD小鼠淀粉样蛋白-β肽水平和斑块负担降低。此外，在PERK+/−·5XFAD小鼠中，CREB功能障碍恢复，同时ATF4上调逆转。总之，这些发现表明PERK可能是一种疾病修饰性治疗靶点，可以预防与AD相关的多种记忆破坏机制。
Emerging evidence suggests that aberrant phosphorylation of eukaryotic initiation factor-2α (eIF2α) may induce synaptic failure and neurodegeneration through persistent translational inhibition of global protein synthesis. However, elevated phospho-eIF2α also paradoxically causes translational activation of a subset of mRNAs such as the β-secretase enzyme BACE1 and CREB repressor ATF4. Therefore, we tested whether genetic reduction of the eIF2α kinase PERK may prevent these deleterious events and mitigate Alzheimer’s disease (AD)-like neuropathology and cognitive impairments in the 5XFAD mouse model. PERK haploinsufficiency blocked overactivation of the PERK-eIF2α pathway, as evidenced by significant reductions in phosphorylation of PERK and eIF2α, in 5XFAD mice. PERK haploinsufficiency was sufficient to rescue memory deficits and cholinergic neurodegeneration in this AD model. Notably, PERK haploinsufficiency also prevented BACE1 elevations, resulting in reduced levels of amyloid-β peptides and plaque burden in 5XFAD mice. Moreover, CREB dysfunction was restored in PERK+/−·5XFAD mice concomitant with reversal of ATF4 upregulation. Together, these findings suggest that PERK may be a disease-modifying therapeutic target to prevent multiple memory-disrupting mechanisms associated with AD.
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影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
16.2
作者：
Chen, A;Muzzio, IA;Kandel, ER
通讯作者：
Kandel, ER
影响因子：
64.8
作者：
Costa-Mattioli, M;Gobert, D;Sonenberg, N
通讯作者：
Sonenberg, N
DOI：
10.1111/j.1460-9568.2009.07031.x
发表时间：
2010-01
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Devi L;Ohno M
通讯作者：
Ohno M