Alterations in somatodendritic bioenergetics in Drosophila models of tauopathy

tau蛋白病果蝇模型体细胞树突生物能学的变化

• 批准号: 10199400
• 负责人: KARTIK VENKATACHALAM
• 金额: $ 115.99万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10199400
• 关键词: Address; Alzheimer' s disease model; Alzheimer' s disease related dementia; Back; Bioenergetics; Ca(2+)-Transporting ATPase; Cell membrane; Cells; Consumption; Coupled; Data; Defect; Dependence; Drosophila genus; Endoplasmic Reticulum; Ensure; Environment; Exhibits; Glutamates; Glycolysis; Goals; Homeostasis; Human; Hydrolysis; ITPR1 gene; Image; Imaging Device; Inositol; Location; Measures; Mediating; Membrane Potentials; Metabolic; Mitochondria; Modeling; Na(+)-K(+)-Exchanging ATPase; Neurodegenerative Disorders; Neurons; Production; Pump; Regulation; Resources; Respiration; Rest; Signal Transduction; Site; Tauopathies; Testing; Toxic effect; Variant; cell type; cytotoxicity; fly; meetings; prevent; receptor; response; stem; tau Proteins

Ionic homeostasis in the somatodendritic compartment of neurons is maintained by pumps that utilize the energy of ATP hydrolysis to set the resting membrane potential and prevent toxic elevations in cytosolic [Ca2+]. The relative contributions of glycolysis and mitochondrial respiration in meeting the ATP burden associated with the activity of these pumps is poorly understood. Also unclear is how these two axes of ATP production are perturbed in neurodegenerative disease such as Alzheimer’s and related dementias (ADRDs), which exhibit bioenergetic deficits and ionic dyshomeostasis. In this proposal, we detail our plans to elucidate the relative contributions of glycolysis and mitochondrial ATP synthesis to the somatodendritic ATP burden stemming with depolarization and the release of Ca2+ from the endoplasmic reticulum (ER). By imaging of cytosolic/mitochondrial [Ca2+] and [ATP]/[ADP] ratio in live dissociated Drosophila neurons we have formulated the model that ATP burden of depolarization is so tightly coupled to ATP synthesis such that somatodendritic [ATP]/[ADP] ratio remained stable in depolarized neurons. Our preliminary data also suggest that depolarization elicits ATP production in the somatodendritic compartment without a necessity for concomitant changes in mitochondrial [Ca2+]. Given that in the absence of matrix [Ca2+] elevations mitochondrial ATP production is not potentiated, we hypothesize that glycolysis, rather than OXPHOS, is the favored bioenergetic response to depolarization. We will test this hypothesis in aim 1, and also determine whether the Na+/K+ ATPase and plasma membrane Ca2+ ATPase (PMCA) are the recipients of glycolysis-derived ATP in depolarized neurons. Aim 2 is driven by our preliminary finding that ER Ca2+ release via inositol trisphosphate receptors (IP3Rs) in depolarized neurons desynchronized ATP production from consumption. We will also probe the significance of Ca2+ transfer between the ER and mitochondria, and attendant changes in neuronal bioenergetics in a fly model of tauopathies, which stem from our preliminary findings show that expression of a toxic human Tau variant in fly glutamatergic neurons disrupted Ca2+ transfer between ER and mitochondria, and evoked toxicity that was consistent with Ca2+ dyshomeostasis. In summary, we will use a range of imaging tools and direct measures of bioenergetics to address fundamental questions of metabolic regulation in neurons, and interrogate the mechanism by which these parameters are perturbed in a model of ADRD.

神经元体树突区室中的离子稳态由利用能量的泵维持 ATP水解，以设置静息膜电位，并防止细胞溶质[Ca 2 +]的毒性升高。的 糖酵解和线粒体呼吸在满足ATP负荷方面的相对贡献， 对这些泵的活性知之甚少。同样不清楚的是，这两个ATP生产轴是如何受到干扰的 在神经变性疾病如阿尔茨海默氏症和相关痴呆（ADRD）中， 缺乏和离子平衡失调。在本提案中，我们详细说明了我们的计划，以阐明 糖酵解和线粒体ATP合成对体树突ATP负荷的影响 以及内质网（ER）中Ca ~（2+）的释放。通过细胞溶质/线粒体[Ca 2 +]和 [ATP]在活的分离的果蝇神经元的ATP/[ADP]比率中，我们已经制定了模型， 去极化与ATP合成紧密相连，体树突[ATP]/[ADP]比值保持稳定 在去极化神经元中。我们的初步数据还表明，去极化刺激ATP的生产， 体树突区室没有必要伴随线粒体[Ca 2 +]的变化。鉴于在 缺乏基质[Ca 2 +]升高线粒体ATP的产生并不增强，我们推测， 糖酵解而不是OXPHOS是对去极化的有利的生物能量响应。我们将测试这个 目的1中的假设，并确定Na+/K+ ATP酶和质膜Ca ~（2+）ATP酶 （PMCA）是去极化神经元中糖酵解衍生的ATP的受体。目标2是由我们的初步驱动 发现去极化神经元通过三磷酸肌醇受体（IP 3Rs）释放ER Ca 2+， 从消费中生产ATP。我们还将探讨钙离子在内质网和内质网之间转移的意义。 线粒体，以及伴随的tau蛋白病苍蝇模型中神经元生物能量学的变化， 我们的初步发现表明，在果蝇神经元中，一种有毒的人类Tau变体的表达被破坏， Ca ~（2+）在内质网和线粒体之间的传递，并诱发与Ca ~（2+）稳态失调一致的毒性。 总之，我们将使用一系列成像工具和生物能量学的直接测量来解决基本问题。 神经元代谢调节的问题，并询问这些参数的机制， 在ADRD模型中受到干扰。

项目成果

p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1.

• DOI: 10.1016/j.isci.2021.102701
• 发表时间: 2021-07-23
• 期刊: iScience
• 影响因子: 5.8
• 作者: Jung J;Liao H;Coker SA;Liang H;Hancock JF;Denicourt C;Venkatachalam K
• 通讯作者: Venkatachalam K

Low doses of the organic insecticide spinosad trigger lysosomal defects, elevated ROS, lipid dysregulation, and neurodegeneration in flies.

• DOI: 10.7554/elife.73812
• 发表时间: 2022-02-22
• 期刊: eLife
• 影响因子: 7.7
• 作者: Martelli F;Hernandes NH;Zuo Z;Wang J;Wong CO;Karagas NE;Roessner U;Rupasinghe T;Robin C;Venkatachalam K;Perry T;Batterham P;Bellen HJ
• 通讯作者: Bellen HJ

Regulation of Aging and Longevity by Ion Channels and Transporters.

• DOI: 10.3390/cells11071180
• 发表时间: 2022-03-31
• 期刊: Cells
• 影响因子: 6
• 作者: Venkatachalam K

Intracellular Lactate Dynamics Reveal the Metabolic Diversity of Drosophila Glutamatergic Neurons.

细胞内乳酸动态揭示果蝇谷氨酸神经元的代谢多样性。

• DOI: 10.1101/2024.02.26.582095
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Price,MatthewS;Moore,TravisI;Venkatachalam,Kartik
• 通讯作者: Venkatachalam,Kartik

Glutamine Produces Ammonium to Tune Lysosomal pH and Regulate Lysosomal Function.

• DOI: 10.3390/cells12010080
• 发表时间: 2022-12-24
• 期刊: Cells
• 影响因子: 6