Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF).
Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF).
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DOI：
10.1016/j.phrs.2015.12.008
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发表时间：
2016-02
影响因子：
9.3
通讯作者：
Allen SJ
中科院分区：
文献类型：
--
作者：
Kailainathan S;Piers TM;Yi JH;Choi S;Fahey MS;Borger E;Gunn-Moore FJ;O'Neill L;Lever M;Whitcomb DJ;Cho K;Allen SJ
该研究描述了脑源性神经营养因子（proBDNF）前形态的两种主要多态性之间的基本功能差异，并解释了为什么这些形式具有如此不同的与年龄相关的神经预后。健康的年轻me66基因携带者（存在于约30%的白种人中）海马体积减少，海马依赖记忆功能受损，但与更常见的Val66基因多态性相比，同样的多态人群在创伤性脑损伤后表现出更强的认知恢复，在衰老过程中表现出延迟的认知功能障碍，患晚发型阿尔茨海默病（AD）的风险更低。为了研究蛋白质多态性在结构、与proBDNF受体结合动力学和体外功能方面的差异，我们生成了纯化的抗切割人类变体。有趣的是，我们发现这些特征没有统计学上的差异。正如预期的那样，proBDNF Val66外源性应用于大鼠海马切片会失调突触可塑性，抑制长期增强（LTP）并促进长期抑郁（LTD）。我们随后观察到这是通过糖原合成酶激酶3β (GSK3β)激活途径发生的。然而，令人惊讶的是，我们发现Met66对LTP和LTD都没有这样的影响。这些新发现表明，与Val66不同，Met66变体不促进突触减弱信号，这可能解释了它对衰老的保护作用。
This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging.