Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies.
Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies.
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DOI：
10.1371/journal.pbio.2001655
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发表时间：
2017-09
期刊：
影响因子：
9.8
通讯作者：
Partridge L
中科院分区：
文献类型：
--
作者：
Augustin H;McGourty K;Allen MJ;Madem SK;Adcott J;Kerr F;Wong CT;Vincent A;Godenschwege T;Boucrot E;Partridge L
降低胰岛素/胰岛素样生长因子（IGF）信号（IIS）可以延长蠕虫、苍蝇和小鼠的健康寿命，但它也可能产生不利影响（“胰岛素悖论”）。慢性、适度降低的IIS通过增加间隙连接蛋白innexin - b对间隙连接（GJs）的靶向作用，挽救了果蝇巨纤维系统（GFS）中与年龄相关的神经传递下降，这是一种简单的逃避反应神经元回路。在培养的人细胞中，当IIS降低时，GJs的内体再循环也受到刺激。此外，增加再循环小鸟苷三磷酸酶（gtpase） Rab4或Rab11的活性，足以在培养的人类细胞和果蝇的IIS升高时维持GJs，并挽救与年龄相关的GJs和GFS功能丧失。因此，降低IIS可提高神经元和其他细胞类型中GJs的内体再循环，指出了治疗性干预衰老相关神经元疾病的细胞机制。胰岛素和胰岛素样生长因子在神经系统发育和功能中起着重要作用。然而，胰岛素信号的减少可以改善不同模式生物中神经退行性疾病的症状，并防止与年龄相关的神经元功能下降，延长寿命。在这里，我们分析了遗传减弱的胰岛素信号对果蝇逃避反应途径的影响。这个简单的神经回路是由间隙连接震动b蛋白组成的电突触控制的，它允许电脉冲在细胞之间传递。众所周知，随着年龄的增长，通过电路的传输速度会减慢。我们发现，在衰老动物中，由于间隙连接蛋白的数量保持，这种功能下降可以通过系统性或电路特异性的胰岛素信号抑制来预防。我们在人细胞培养系统中的实验表明，在胰岛素水平降低的条件下，通过小蛋白Rab4和Rab11，间隙连接蛋白的膜靶向性增加。我们还发现，增加果蝇体内这些循环介导蛋白的水平，可以保留老年果蝇的逃逸反应回路输出，并提出了改善衰老过程中由电突触主导的神经元回路功能的方法。
Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the “insulin paradox”). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders. Insulin and insulin-like growth factors play an important role in the nervous system development and function. Reduced insulin signaling, however, can improve symptoms of neurodegenerative diseases in different model organisms and protect against age-associated decline in neuronal function extending lifespan. Here, we analyze the effects of genetically attenuated insulin signaling on the escape response pathway in the fruit fly Drosophila melanogaster. This simple neuronal circuit is dominated by electrical synapses composed of the gap junctional shaking-B protein, which allows for the transfer of electrical impulses between cells. Transmission through the circuit is known to slow down with age. We show that this functional decline is prevented by systemic or circuit-specific suppression of insulin signaling due to the preservation of the number of gap junctional proteins in aging animals. Our experiments in a human cell culture system reveal increased membrane targeting of gap junctional proteins via small proteins Rab4 and Rab11 under reduced insulin conditions. We also find that increasing the level of these recycling-mediating proteins in flies preserves the escape response circuit output in old flies and suggests ways of improving the function of neuronal circuits dominated by electrical synapses during aging.
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影响因子：
9.8
作者：
Fayyazuddin A;Zaheer MA;Hiesinger PR;Bellen HJ
通讯作者：
Bellen HJ
影响因子：
3.3
作者：
Dickstein, D. L.;Weaver, C. M.;Luebke, J. I.;Hof, P. R.
通讯作者：
Hof, P. R.
DOI：
10.1111/j.1460-9568.2007.05686.x
发表时间：
2007-07
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Allen MJ;Murphey RK
通讯作者：
Murphey RK
影响因子：
7.4
作者：
Bulteau, AL;Moreau, M;Friguet, B
通讯作者：
Friguet, B
影响因子：
16.2
作者：
Gazit N;Vertkin I;Shapira I;Helm M;Slomowitz E;Sheiba M;Mor Y;Rizzoli S;Slutsky I
通讯作者：
Slutsky I