Molecular and genetic studies of NMNAT2 in neuroprotection

NMNAT2 神经保护作用的分子和遗传学研究

• 批准号: 10579950
• 负责人: HUI-CHEN LU
• 金额: $ 51.27万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579950
• 关键词: ALS patients; Acceleration; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapy; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Attenuated; Axon; Axonal Transport; Bayesian Analysis; Biology; Brain; Bypass; Central Nervous System; Chronic; Compensation; Data; Defect; Development; Disease model; Down-Regulation; Energy Supply; Enzymes; Face; Financial cost; Genes; Genetic study; Gliosis; Glucose; Glutamate-ammonia-ligase adenylyltransferase; Glutamates; Glycolysis; Goals; Golgi Apparatus; Health; Hippocampus; Homeostasis; Human; Huntington Disease; Hyperactivity; Image; Impairment; Inflammation; Knockout Mice; Knowledge; Life; Link; Maintenance; Metabolic; Metabolic Pathway; Metabolism; Molecular; Molecular Chaperones; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Oxidative Phosphorylation; Parkinson Disease; Pathology; Pentosephosphates; Phenotype; Play; Prevalence; Process; Proteins; Proteolytic Processing; Resolution; Risk Factors; Role; Spinal Cord; Supplementation; Synaptic Transmission; Synaptic Vesicles; Testing; Therapeutic; Time; Up-Regulation; Visualization; amyloid precursor protein processing; axonal degeneration; axonopathy; brain metabolism; cofactor; cognitive function; combat; design; drug discovery; fast axonal transport; glucose metabolism; hyperphosphorylated tau; in vivo; insight; metabolomics; neuroinflammation; neuroprotection; nicotinamide riboside supplementation; novel; novel therapeutic intervention; prevent; programs; public health relevance; response; sensor; social; synaptogenesis; tau Proteins; theories; therapeutic target; therapy development

PROJECT SUMMARY / ABSTRACT The high and increasing prevalence as well as the staggering social and financial costs of Alzheimer’s Disease (AD) and AD-related dementia (ADRD) emphasize the importance of finding strategies to prevent or slow their progression. Here we aim to elucidate the basic biology of neuronal maintenance and energy homeostasis to enable us to design new therapeutic strategies independent of tau or beta-amyloid theories. Almost all neurons are born early in life and require an active neuroprotection program for their survival in response to the myriad of internal and external challenges they face throughout life. NMNAT2 is a bifunctional protein that we and others have identified as an important neuronal maintenance factor. NMNAT2 synthesizes nicotinamide mononucleotide (NAD+) and serves as a molecular chaperone for day-to-day axonal function and to protect neurons from proteinopathies such as hyperphosphorylated tau. In AD patients, NMNAT2 abundance is greatly reduced to less than 50% of normal level and its level correlates with cognitive function. We found that deleting NMNAT2 from mouse cortical glutamatergic neurons results in AD/ADRD-like phenotypes, such as glucose hypometabolism, axonopathy and neuroinflammation. The current mouse and human results strongly support a causal relationship between NMNAT2 hypofunction and neurodegeneration. Axonal degeneration is a key step in AD/ADRD and many neurodegenerative diseases. Axonal transport plays critical roles in neuronal function and survival and is extremely energy demanding. Abnormal axonal transport is an early defect in axons destined to degenerate. Increasing evidence reveals dysregulated glucose metabolism in AD. Our preliminary studies suggest that NMNAT2 plays a critical role in fast axonal transport by maintaining axonal energy homeostasis. Deleting NMNAT2 in glutamatergic neurons reduces glycolysis while at the same time augmenting the pentose phosphate. These findings raise the following questions: Does NMNAT2 in glutamatergic neurons play essential roles in maintaining energy homeostasis for normal axonal function? Does glucose hypometabolism caused by loss of NMNAT2 cause axonopathy? Will supplement strategies bypassing NMNAT2 support neurons and attenuate axonopathy? To answer these questions, we propose the following aims: 1. Test the hypothesis that NMNAT2 is required in cortical neurons for axonal transport. 2. Test the hypothesis that NMNAT2 contributes to axonal energy homeostasis. 3. Test the hypothesis that NMNAT2 in cortical neurons is essential for glucose metabolism The knowledge gained from our proposed studies will help us gain mechanistic understanding into how NMNAT2 contributes to active neuronal maintenance and will provide necessary insights to assist in drug discovery using NMNAT2 as a therapeutic target for neurodegeneration.

项目摘要/摘要