NAD+ metabolism and signaling in ALS models

ALS 模型中的 NAD 代谢和信号传导

• 批准号: 10455545
• 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
• 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/10455545
• 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; Oxides; Paralysed; Patients; Phenotype; Play; Poly(ADP-ribose) Polymerases; 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; nicotinamide-beta-riboside; novel therapeutic intervention; overexpression; protein TDP-43; riboside; superoxide dismutase 1; therapeutic target

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利用机制见解开发新的治疗策略