Linking metabolism, neural function, and aging

描述(由申请人提供)：新陈代谢、衰老和神经功能之间有基本的联系。考虑到神经系统集中协调有机体的新陈代谢，因此，了解神经系统评估有机体能量状态的精确机制是理解衰老和老年疾病的基础。通过色氨酸降解途径(也称为犬尿氨酸途径)的通量变化与各种神经退行性疾病有关，如亨廷顿氏症、阿尔茨海默氏症、多发性硬化症和肌萎缩侧索硬化症，以及精神分裂症和抑郁症等精神疾病。在不同时间点阻断色氨酸降解途径可改善小鼠、果蝇和线虫的神经退化或蛋白质聚集模型。一种氨基酸降解途径如何影响如此广泛的神经过程仍然是一个谜。在研究线虫摄食调节途径的过程中，我们有了一个意想不到的发现，一种特定的犬尿氨酸途径代谢产物犬尿酸在动物的神经系统中局部产生，并作为衡量食物可获得性的内源性指标。我们的初步遗传和生化研究通过谷氨酸能信号通路将这种代谢物连接到5-羟色胺的释放，而5-羟色胺的释放反过来又调节包括胰岛素在内的神经内分泌分泌。这是通过5-羟色胺能抑制特定神经元中的AMP激活的激酶来实现的。由于色氨酸是一种必需的氨基酸，而且各种色氨酸衍生的代谢物具有神经信号传递特性，我推测犬尿氨酸途径代谢物是一种古老的机制，它将代谢与神经功能联系起来，包括神经内分泌分泌，协调新陈代谢、蛋白质动态平衡和衰老的相互交织的路径。我建议使用线虫来描述将犬尿酸水平与衰老和蛋白质动态平衡的神经内分泌机制联系起来的分子回路。我们将首先建立犬尿酸和特定神经元的胰岛素分泌之间的精确分子联系，研究这一神经通路对整个生物体范围的蛋白平衡机制的影响，并确定犬尿酸通路与各种长寿突变体之间的调控关系。总而言之，这些研究将成为神经系统如何感知新陈代谢以调节与年龄相关的过程的范例。

DESCRIPTION (provided by applicant): There is a fundamental connection between metabolism, aging, and neural functions. Considering that the nervous system centrally coordinates organismal metabolism and therefore its sequale, understanding the precise mechanisms through which the nervous system assesses organismal energetic state is fundamental to understanding aging and age on-set diseases. Changes in flux through the tryptophan degradation pathway, also known as the kynurenine pathway, have been linked to a variety of neurodegenerative diseases such as Huntington's, Alzheimer's, multiple sclerosis and amyotrophic lateral sclerosis as well as psychiatric disorders such as schizophrenia and depression. Blocking the tryptophan degradation pathway at various points ameliorates murine, Drosophila, and C. elegans models of neurodegeneration or protein aggregation. How one amino acid degradation pathway affects such a broad range of neurological processes remains a mystery. In the course of studying C. elegans feeding regulatory pathways, we made the unexpected discovery that a specific kynurenine pathway metabolite, kynurenic acid, is locally produced within the animal's nervous system and serves as an endogenous measure of food availability. Our preliminary genetic and biochemical studies connect this metabolite through a glutamatergic signaling pathway to serotonin release, which in turn, modulates neuroendocrine secretions including that of insulin. This is accomplished through serotonergic inhibition of AMP-activated kinase in specific neurons. As tryptophan is an essential amino acid and various tryptophan- derived metabolites have neural signaling properties, I hypothesize that the kynurenine pathway metabolites are an ancient mechanism that links metabolism to neural functions including neuroendocrine secretions that coordinate the intertwined pathways of metabolism, protein homeostasis, and aging. I propose to use C. elegans to delineate the molecular circuits that link kynurenic acid levels to neuroendocrine mechanisms of aging and protein homeostasis. We will first establish the precise molecular links between kynurenic acid and insulin secretion from specific neurons, investigate the consequences of this neural pathway on organism-wide mechanisms of proteostasis, and define the regulatory relationships between the kynurenine pathway and various longevity mutants. Together, these studies will be a paradigm for how metabolism is sensed by the nervous system to regulate age related processes.