NAD+ metabolism and signaling in ALS models

ALS 模型中的 NAD 代谢和信号传导

基本信息

批准号：
10670737
负责人：
Marcelo R Vargas
金额：
$ 36.23万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670737
关键词：
ADP-ribosyl Cyclase ALS pathology ALS patients Adult Amyotrophic Lateral Sclerosis Animal Model Antioxidants Astrocytes Autopsy Biological Process Brain Stem Cause of Death Cellular biology Cessation of life Coculture Techniques Code Consumption DNA Repair Data Development Dietary Supplementation Disease Disease Progression Enzymes Exposure to Family Funding Genes Genetic Transcription Goals Human Immune response Inflammation Inherited Investigation Lead Link Metabolic Metabolism Modeling Modification Molecular Molecular Profiling Motor Cortex Motor Neurons Movement Mus Muscle Muscle Weakness Mutate Mutation NADH Nerve Degeneration Neuroglia Neurons Niacinamide Nicotinamide adenine dinucleotide Nucleotides Oxidation-Reduction Oxidative Stress Paralysed Patients Phenotype Play Polymerase Process Protein Family Publishing Reaction Resistance Rodent Rodent Model Role SIRT1 gene Signal Pathway Signal Transduction Sirtuins Spinal Cord Symptoms System Therapeutic Time Tissues Toxic Environmental Substances Toxic effect Transferase Translating United Kingdom United States cell type circadian deacylation experimental study familial amyotrophic lateral sclerosis gain of function genetic pedigree genetic signature in vivo insight mitochondrial metabolism motor neuron degeneration mouse model mutant nerve stem cell neuron loss neuroprotection nicotinamide-beta-riboside novel therapeutic intervention overexpression protein TDP-43 riboside superoxide dismutase 1 therapeutic target

项目摘要

The long-term goal of the proposal is to develop new therapeutic strategies using mechanistic insights drawn from understanding astrocyte-motor neuron interaction in amyotrophic lateral sclerosis (ALS). In particular, the primary objective of this proposal is to better delineate the mechanisms responsible for the protection conferred by enhancing nicotinamide adenine dinucleotide (NAD+) availability in ALS models. ALS or Lou Gehrig's disease accounts for about 1 in 500 to 1 in 1,000 adult deaths in the United States and is caused by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Motor neuron death leads to muscle weakness and paralysis causing death in one to five years from the time of symptoms onset. Most ALS cases are sporadic (SALS) and exposure to yet unidentified environmental toxicants might be responsible for SALS. About 5-10% of the cases are inherited (familial ALS, FALS) but FALS and SALS are phenotypically indistinguishable, and a significant share of our understanding come from the study of rodent models over-expressing ALS-linked mutant human superoxide dismutase 1 (hSOD1). Several lines of evidence underscored the contribution of non-neuronal cells in the neurodegenerative process and astrocytes appear to have a decisive role in the progression of the disease. Accordingly, primary astrocytes isolated from mutant hSOD1 over-expressing mice induce motor neuron death in co-culture, and it has been demonstrated that astrocytes differentiated from spinal cord autopsy-derived neuronal progenitor cells from FALS and SALS patients are also toxic for motor neurons in co-culture. We have shown that over-expression of the NAD+-synthesizing enzyme, NAMPT, or increasing the activity of two sirtuins (SIRT3 and/or SIRT6) is protective in a co-culture model of ALS. Sirtuins are a family of enzymes capable of catalyzing NAD+-dependent deacylation and mono(ADPribosyl)ation reactions, and play a key role in transcription, DNA repair, metabolism, and oxidative stress resistance. Our previously published data and ongoing experiments demonstrate that modulating NAD+ metabolism and signaling is protective in a co-culture model of ALS, while the expression of enzymes involved in NAD+ synthesis and NAD+-dependent signaling is altered in ALS patients. Moreover, enhancing NAD+ levels by dietary supplementation with a metabolic precursor (nicotinamide riboside) exerts neuroprotective effects in an ALS mouse model. Thus, we seek to better define the role of NAD+-dependent signaling during motor neuron degeneration. The results obtained during the previous funding period rationally support the development of cell-type specific approaches to better target NAD+ metabolism and signaling in ALS. Since we have shown that therapeutic targets identified in our astrocyte-motor neuron co-culture system have a beneficial effect when translated into animal models of ALS, the proposal is likely to provide a mechanistic insight and in vivo proof of the value of modulating NAD+ metabolism and signaling as a therapeutic approach in ALS.

该提案的长期目标是使用机械见解制定新的治疗策略从了解肌萎缩性侧索硬化症（ALS）中的星形胶质细胞运动神经元相互作用中得出。在特别是，该提案的主要目的是更好地描述负责的机制通过在ALS模型中增强烟酰胺腺嘌呤二核苷酸（NAD+）的可用性，赋予保护。 ALS 或Lou Gehrig氏病在美国约为500至1,000名成年人死亡中的1,000至1个由脊髓，脑干和运动皮层中运动神经元的进行性变性引起的。运动神经元死亡会导致肌肉无力和瘫痪，从而导致死亡。症状发作。大多数ALS案件是零星（萨尔）和尚未确定的环境有毒物质可能是造成萨尔奶油的原因。大约5-10％的案件是继承的（家族性ALS，fals），但伪造和萨尔斯在表型上是无法区分的，我们的理解中的很大一部分来自啮齿动物模型过表达ALS连接的突变体超氧化物歧化酶1（HSOD1）的研究。几条证据强调了神经退行性过程中非神经元细胞的贡献星形胶质细胞似乎在疾病的进展中起决定性作用。因此，主要从突变体HSOD1过表达的小鼠中分离出的星形胶质细胞会诱导共培养中的运动神经元死亡，并且已证明星形胶质细胞与脊髓尸检衍生的神经元祖细胞区分开来自伪造和萨尔斯患者的细胞也对共培养中的运动神经元有毒。我们已经表明，NAD+ - 同一酶，NAMPT或增加两个Sirtuins的活性（SIRT3和/或 SIRT6）在ALS的共培养模型中具有保护性。 Sirtuins是一个能够催化NAD+依赖性的脱酰化和单声道（adpribosyl）反应的酶家族，并且在转录，DNA修复中起关键作用，代谢和氧化应激抗性。我们先前发布的数据和正在进行的实验证明调节NAD+代谢和信号传导在ALS的共培养模型中具有保护性，而 ALS中涉及NAD+合成和NAD+依赖性信号的酶的表达发生了变化患者。此外，用代谢前体补充饮食来增强NAD+水平（烟酰胺核苷）在ALS小鼠模型中发挥神经保护作用。因此，我们试图更好地定义 NAD+依赖性信号传导在运动神经元变性中的作用。在以前的资金期合理地支持细胞类型的特定方法以更好的目标 NAD+代谢和ALS信号传导。由于我们已经证明了在我们的当翻译成ALS的动物模型时，星形胶质细胞运动神经元共培养系统具有有益的作用，该提议可能会提供机械洞察力和体内证明调节NAD+的价值代谢和信号作为ALS的治疗方法。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

FABP7 upregulation induces a neurotoxic phenotype in astrocytes.

DOI：
10.1002/glia.23879
发表时间：
2020-12
期刊：
Glia
影响因子：
6.2
作者：
Killoy KM;Harlan BA;Pehar M;Vargas MR
通讯作者：
Vargas MR

Altered expression of clock and clock-controlled genes in a hSOD1-linked amyotrophic lateral sclerosis mouse model.

DOI：
10.1096/fj.202000386rr
发表时间：
2021-03
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Killoy KM;Pehar M;Harlan BA;Vargas MR
通讯作者：
Vargas MR

Electrophilic nitro-fatty acids prevent astrocyte-mediated toxicity to motor neurons in a cell model of familial amyotrophic lateral sclerosis via nuclear factor erythroid 2-related factor activation.

DOI：
10.1016/j.freeradbiomed.2016.03.013
发表时间：
2016-06
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Diaz-Amarilla P;Miquel E;Trostchansky A;Trias E;Ferreira AM;Freeman BA;Cassina P;Barbeito L;Vargas MR;Rubbo H
通讯作者：
Rubbo H

NR1D1 downregulation in astrocytes induces a phenotype that is detrimental to cocultured motor neurons.

DOI：
10.1096/fj.202101275r
发表时间：
2022-04
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
通讯作者：

Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration.

DOI：
10.1089/ars.2017.7145
发表时间：
2017-06
期刊：
Antioxidants & redox signaling
影响因子：
6.6
作者：
Mariana Pehar;Benjamin Harlan;Kelby M. Killoy;Marcelo R Vargas
通讯作者：
Mariana Pehar;Benjamin Harlan;Kelby M. Killoy;Marcelo R Vargas

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Marcelo R Vargas其他文献

Modulation of p75NTR‐dependent motor neuron death by a small non‐peptidyl mimetic of the neurotrophin loop 1 domain

神经营养素环 1 结构域的小型非肽基模拟物调节 p75NTR 依赖性运动神经元死亡

DOI：
10.1111/j.1460-9568.2006.05040.x
发表时间：
2006
期刊：
European Journal of Neuroscience
影响因子：
3.4
作者：
Mariana Pehar;P. Cassina;Marcelo R Vargas;Youmei Xie;Joseph S Beckman;S. Massa;F. Longo;L. Barbeito
通讯作者：
L. Barbeito