LKB1 and AMPK regulate synaptic remodeling in old age.
LKB1 and AMPK regulate synaptic remodeling in old age.
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DOI：
10.1038/nn.3772
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发表时间：
2014-09
影响因子：
25
通讯作者：
Sanes JR
中科院分区：
文献类型：
--
作者：
Samuel MA;Voinescu PE;Lilley BN;de Cabo R;Foretz M;Viollet B;Pawlyk B;Sandberg MA;Vavvas DG;Sanes JR
神经功能的降低部分是由于突触的改变。为了确定导致这种变化的分子缺陷，我们专注于外层视网膜，其中突触在老年啮齿动物和人类中发生了显着变化。我们发现，丝氨酸/苏氨酸激酶LKB 1和它的底物之一，AMPK，调节这个过程。在老年小鼠中，突触重塑伴随着总LKB 1和活性（磷酸化）AMPK水平的特异性降低。在没有任何激酶的情况下，年轻的成年小鼠出现了与老年野生型动物相似的视网膜缺陷。LKB 1和AMPK在视杆细胞中起作用，它们的缺失导致异常的轴突回缩、突触后树突的延伸和异位突触的形成。相反地，增加AMPK活性在遗传上或遗传上减弱并可能逆转与年龄相关的突触改变。总之，这些结果确定了与年龄相关的突触重塑的分子决定因素，并提出了减轻这些变化的策略。
Age-related decreases in neural function result in part from alterations in synapses. To identify molecular defects that lead to such changes, we focused on the outer retina, in which synapses are markedly altered in old rodents and humans. We found that the serine/threonine kinase LKB1 and one of its substrates, AMPK, regulate this process. In old mice, synaptic remodeling was accompanied by specific decreases in the levels of total LKB1 and active (phosphorylated) AMPK. In the absence of either kinase, young adult mice developed retinal defects similar to those that occurred in old wild-type animals. LKB1 and AMPK function in rod photoreceptors where their loss leads to aberrant axonal retraction, the extension of postsynaptic dendrites and the formation of ectopic synapses. Conversely, increasing AMPK activity genetically or pharmacologically attenuates and may reverse age-related synaptic alterations. Together, these results identify molecular determinants of age-related synaptic remodeling and suggest strategies for attenuating these changes.