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

基本信息

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
项目类别：
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

项目摘要

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.

神经元体树突室中的离子稳态由利用能量的泵维持 ATP 水解以设定静息膜电位并防止胞质 [Ca2+] 中的毒性升高。糖酵解和线粒体呼吸在满足与 ATP 相关的负担方面的相对贡献人们对这些泵的活动知之甚少，同时还不清楚 ATP 生成的这两个轴是如何受到干扰的。神经退行性疾病，例如阿尔茨海默病和相关痴呆症 (ADRD)，这些疾病表现出生物能在本提案中，我们详细说明了阐明以下各项的相对贡献的计划。糖酵解和线粒体 ATP 合成对体细胞树突 ATP 负荷的影响源于去极化以及内质网 (ER) 中 Ca2+ 的释放通过胞质/线粒体 [Ca2+] 成像和活体分离果蝇神经元中的 [ATP]/[ADP] 比率我们制定了模型，ATP 负担去极化与 ATP 合成紧密耦合，使得体细胞树突 [ATP]/[ADP] 比率保持稳定我们的初步数据还表明，去极化会引起 ATP 的产生。体细胞树突室不需要线粒体 [Ca2+] 的伴随变化。缺乏基质 [Ca2+] 会增加线粒体 ATP 的产生，我们发现糖酵解，而不是 OXPHOS，是最受青睐的去极化生物能反应，我们将对此进行测试。目标 1 中的假设，并确定 Na+/K+ ATP 酶和质膜 Ca2+ ATP 酶是否 (PMCA) 是去极化神经元中糖酵解衍生的 ATP 的接受者，目标 2 是由我们的初步驱动的。发现去极化神经元中内质网 Ca2+ 通过肌醇三磷酸受体 (IP3R) 释放不同步我们还将探讨内质网和内质网之间 Ca2+ 转移的重要性。线粒体，以及随之而来的 tau蛋白病果蝇模型中神经元生物能的变化，这些变化源于我们的初步研究结果表明，果蝇谷氨酸能神经元中有毒的人类 Tau 蛋白变体的表达被破坏 Ca2+ 在内质网和线粒体之间转移，并引起与 Ca2+ 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 ADRD 模型中受到扰动。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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
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

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