Neuropathology in tauopathies stem from depolarization-induced alterations in the planar distribution of phosphoinositides

tau蛋白病的神经病理学源于去极化引起的磷酸肌醇平面分布的改变

• 批准号: 10055299
• 负责人: KARTIK VENKATACHALAM
• 金额: $ 178.83万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055299
• 关键词: Acyltransferase; Alzheimer' s Disease; Alzheimer' s disease related dementia; Animals; Attenuated; Autophagocytosis; C9ORF72; Cell membrane; Cells; Chronic; Coupled; Coupling; Data; Data Set; Development; Drosophila genus; Electrophysiology (science); Enzymes; Epigenetic Process; Estrogen receptor positive; Event; Eye; Functional disorder; Genes; Genetic Transcription; Glutamates; Hydrolysis; Inositol; Lead; Lipids; Longevity; Mediating; Membrane Potentials; Modeling; Mus; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Outcome; Pathologic; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipase; Population; Potassium Channel; Process; Production; Proteins; RNA analysis; Receptor Activation; Receptor Signaling; Regulation; Rest; Second Messenger Systems; Side; Signal Transduction; Tauopathies; Technology; Testing; Toxic effect; Transgenes; attenuation; base; causal variant; fly; gene repression; insight; knock-down; mitochondrial dysfunction; multidisciplinary; neuroinflammation; neuron loss; neuropathology; neurotoxicity; novel; preference; premature; prevent; receptor; restoration; stem; tau Proteins; tau aggregation; tau mutation; therapeutic target; transcriptome sequencing

Tau tangles are common features of Alzheimer’s disease related dementias (ADRDs) and induce a range of pathological perturbations in neurons including hyperexcitability and Ca2+ dyshomeostasis. In this application, we use Drosophila to demonstrate that progressive neurotoxicity elicited by Tau or hexanucleotide repeat expansion of C9ORF72 involves elevated production of the second messenger, inositol trisphosphate (IP3), and activation of IP3 receptor (IP3R)-mediated ER Ca2+ release. Thus, premature lethality stemming from expression of ADRD-causing transgenes was almost fully suppressed by attenuation of IP3 production or knockdown IP3Rs. Although IP3Rs have been previously implicated in neurodegeneration, we have uncovered a novel mechanism underlying channel hyperactivation. We show expression of ADRD-causing transgenes leads to loss of neuronal membrane potential, and that the resulting depolarization is what increases IP3R activity. Our preliminary findings are consistent with the notion that depolarization increases association of an enzyme responsible for IP3 production, phospholipase Cb (PLCb), with its phosphoinositide substrate, PIP2. Greater PLCb–PIP2 interactions in depolarized cells lead to elevated IP3 production upon stimulation of PLCb-coupled receptors. In Aim 1, we will test the aforementioned hypothesis in fly and mouse neurons expressing mutant tau. We also ask how ADRD neurons lose their ability to maintain membrane potential. Based on electrophysiological recordings and analyses of RNA-seq datasets, we hypothesize that chronic depolarization stems from diminished abundance of neuronal K+ leak channels that are needed for establishing normal resting membrane potential. In Aim 2, we seek to determine how depolarization potentiates PLCb–IP3R signaling. Our findings suggest that membrane potential dependent regulation of PLCb—PIP2 association and hydrolysis depend on the lipids’ acyl side chains. Taken in conjunction with our findings that depolarization promotes IP3 production, we hypothesize that PLCb activity depends on PIP2 side chain identity, and increases in depolarized cells due to the preferential hydrolysis of species with longer and more unsaturated side chains. Successful completion of the proposed studies would demonstrate that IP3R hyperactivation in ADRD neurons is agnostic to the causal mutations — an insight that speaks to the wide applicability of our findings. We also hope to develop strategies that can be leveraged to selectively change the population of PIP2 species at the plasma membrane in order to correct pathological Ca2+ dyshomeostasis that occurs in ADRD.

Tau蛋白缠结是阿尔茨海默病相关痴呆（adrd）的共同特征，并诱导一系列