The SIRT1-Gpd1L-NAD+ interactome in regulation of the Neuronal Sodium Channel: Implications for Cognitive Impairment of Alzheimerâs Dementia

SIRT1-Gpd1L-NAD 相互作用组对神经元钠通道的调节：对阿尔茨海默氏痴呆认知障碍的影响

• 批准号: 10117944
• 负责人: Kaikobad J. Irani
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117944
• 关键词: Acetylation; Action Potentials; Adult; Affect; Alzheimer' s Disease; Amino Acids; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Antibodies; Arrhythmia; Axon; Bioenergetics; Brain; Cardiac; Cardiac Myocytes; Cell surface; Cells; Clinical Research; Cognitive deficits; Creatine Kinase; Custom; Cytochromes b; Cytoplasmic Granules; Data; Deacetylase; Dementia; Development; Disease; Down-Regulation; Electrophysiology (science); Enzymes; Glycerol; Glycerol-3-Phosphate Dehydrogenase; Homeostasis; Homologous Gene; Hypoxia; Impaired cognition; Ion Channel; Link; Lysine; Mediating; Metabolism; Methodology; Mitochondria; Modeling; Molecular; Motor Neurons; Mus; Neuraxis; Neuroglia; Neurons; Nicotinamide adenine dinucleotide; Oxidoreductase; Pathologic; Patients; Peptides; Physiology; Play; Post-Translational Protein Processing; Property; Purkinje Cells; Reagent; Regulation; Role; SIRT1 gene; Schwann Cells; Senile Plaques; Sequence Homology; Sodium; Sodium Channel; Surface; Transgenic Animals; Work; abeta toxicity; base; clinically relevant; density; enzyme pathway; falls; heart electrical activity; heart function; hippocampal pyramidal neuron; insight; knock-down; metabolome; mouse model; neuronal excitability; neuronal metabolism; neuropathology; novel; parent grant; preclinical development; risk variant; tool; trafficking; voltage

Neuronal hyperexcitability contributes to the cognitive defects in Alzheimer's Dementia (AD). However, the mechanisms underlying neuronal hyperexcitability are not well understood. Development of AD is also preceded by decrease in neuronal metabolism. Hypometabolism in AD is associated with downregulation of enzymes important in energy homeostasis, among which is the hypoxia-sensitive enzyme Glycerol-3-phosphate dehydrogenase-like-1 (Gpdl1) which has an important place in the nicotinamide adenine dinucleotide (NAD+) metabolome in cells. However, the integrative cellular/molecular mechanisms linking change in NAD+ metabolome to neuronal excitability are also poorly understood. Our prior work has shown the role of the NAD+-dependent Sirtuin1 lysine deacetylase regulates acetylation and properties of the cardiac voltage-gated sodium channel Nav1.5. Moreover, we preliminary data in the parent grant shows that Gpd1L governs Nav1.5. Based on this work, the parent grant proposes to determine how the interaction between Gpd1l, Sirtuin1 and the NAD+ metabolome regulates the cardiac sodium channel and cardiac electrical activity In this supplement we will apply this approach to investigate the role of Gpd1l, Sirtuin1 and the NAD+ metabolome in regulation of the neuronal voltage-gated sodium channel (Nav1.6). Nav1.6 is a close homolog of Nav1.5 and is integral to neuronal excitation. β-amyloid (Aβ) peptides which play a causal role in Alzheimer's dementia, stimulate Nav1.6 expression and activity. Because voltage-gated sodium channels are highly conserved and have significant homology in key regulatory residues and domains, we hypothesize that Gpd1l, Sirtuin1 and the NAD+ metabolome interact to affect Nav1.6 expression and function, similar to their effect on Nav1.5, and thus play a part in modulating neuronal excitability. The application will use state-of-the-art electrophysiological methodologies, as well as novel reagents we have generated for the parent grant, including genetically modified Gpd1l and Sirt1 mice, reagents to manipulate the NAD+ metabolome, and custom antibody toward acetylated voltage-gated sodium channels. Thus, this application falls within the scope of the parent grant. It will explore whether the Gpd1l-Sirtuin1-NAD+ interactome can modulate neuronal excitability in the context of β-amyloid toxicity through their impact on the post-translational landscape, surface expression, and conductance properties of Nav1.6. These studies will open a new chapter in understanding the metabolo-molecular basis of neuronal sodium channel excitability, dysregulation of which plays a vital role in cognitive impairment of AD.

神经元过度兴奋导致阿尔茨海默氏痴呆（AD）的认知缺陷。 然而，神经元过度兴奋的机制还不清楚。 AD的发展也先于神经元代谢的减少。低代谢 AD与能量稳态中重要的酶的下调有关，其中 是缺氧敏感酶甘油-3-磷酸脱氢酶样-1（Gpdl 1）， 在细胞中的烟酰胺腺嘌呤二核苷酸（NAD+）代谢组中的重要位置。 然而，将NAD+代谢组的变化与 神经元兴奋性也知之甚少。 我们先前的工作已经显示了NAD+依赖性Sirtuin 1赖氨酸脱乙酰酶调节 心脏电压门控钠通道Nav1.5的乙酰化和性质。而且我们 母基金的初步数据显示，Gpd 1 L支配Nav1.5。基于这项工作， 父母补助金建议确定Gpd 1 l，Sirtuin 1和NAD+之间的相互作用 代谢组调节心脏钠通道和心脏电活动 在本补充中，我们将应用这种方法来研究Gpd 1 l，Sirtuin 1和 NAD+代谢组在神经元电压门控钠通道（Nav1.6）的调节。NAV1.6 是Nav1.5的紧密同系物，是神经元兴奋的组成部分。β-淀粉样蛋白（Aβ）肽， 在阿尔茨海默氏痴呆症中发挥因果作用，刺激Nav1.6的表达和活性。因为 电压门控钠离子通道是高度保守的，在关键蛋白质上具有显著的同源性。 调节残基和结构域，我们假设Gpd 1 l，Sirtuin 1和NAD+代谢组 相互作用以影响Nav1.6表达和功能，类似于它们对Nav1.5的作用，从而发挥 参与调节神经元兴奋性。 该应用程序将使用最先进的电生理学方法，以及新颖的 我们为母基金生产的试剂，包括转基因的Gpd 1 l和Sirt 1 小鼠，操纵NAD+代谢组的试剂，以及针对乙酰化的定制抗体， 电压门控钠通道因此，本申请福尔斯属于母公司补助金的范围。 它将探索Gpd 1 l-Sirtuin 1-NAD+相互作用组是否可以调节神经元的兴奋性， β-淀粉样蛋白毒性通过其对翻译后景观的影响，表面 表达和Nav1.6的电导性质。这些研究将开启新的篇章， 了解神经元钠通道兴奋性的代谢分子基础， 其调节异常在AD的认知损害中起重要作用。