Unique tau- and synuclein-dependent metabolic reprogramming in neurons distinct from normal aging

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Aging Cell Pub Date : 2024-08-13 DOI:10.1111/acel.14277
Shweta Yadav, Aidan Graham, Farazdaq Al Hammood, Chris Garbark, Deepika Vasudevan, Udai Pandey, John M. Asara, Dhivyaa Rajasundaram, Andrey A. Parkhitko
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Abstract

Neuronal cells are highly specialized cells and have a specific metabolic profile to support their function. It has been demonstrated that the metabolic profiles of different cells/tissues undergo significant reprogramming with advancing age, which has often been considered a contributing factor towards aging-related diseases including Alzheimer's (AD) and Parkinson's (PD) diseases. However, it is unclear if the metabolic changes associated with normal aging predispose neurons to disease conditions or a distinct set of metabolic alterations happen in neurons in AD or PD which might contribute to disease pathologies. To decipher the changes in neuronal metabolism with age, in AD, or in PD, we performed high-throughput steady-state metabolite profiling on heads in wildtype Drosophila and in Drosophila models relevant to AD and PD. Intriguingly, we found that the spectrum of affected metabolic pathways is dramatically different between normal aging, Tau, or Synuclein overexpressing neurons. Genetic targeting of the purine and glutamate metabolism pathways, which were dysregulated in both old age and disease conditions partially rescued the neurodegenerative phenotype associated with the overexpression of wildtype and mutant tau. Our findings support a “two-hit model” to explain the pathological manifestations associated with AD where both aging- and Tau/Synuclein- driven metabolic reprogramming events cooperate with each other, and targeting both could be a potent therapeutic strategy.

Abstract Image

Abstract Image

有别于正常衰老的神经元中独特的 tau 和突触核蛋白依赖性代谢重编程。
神经细胞是高度特化的细胞,具有特定的代谢特征以支持其功能。有研究表明,随着年龄的增长,不同细胞/组织的代谢特征会发生显著的重编程,这通常被认为是导致阿尔茨海默氏症(AD)和帕金森氏症(PD)等衰老相关疾病的一个因素。然而,目前还不清楚与正常衰老相关的新陈代谢变化是否会使神经元易患疾病,或者在阿尔茨海默病或帕金森病的神经元中会发生一系列不同的新陈代谢变化,而这些变化可能会导致疾病病理变化。为了解读神经元代谢随年龄、AD 或 PD 的变化,我们对野生型果蝇和与 AD 和 PD 相关的果蝇模型的头部进行了高通量稳态代谢物谱分析。有趣的是,我们发现在正常衰老、Tau 或突触核蛋白过表达的神经元中,受影响的代谢通路的谱系大不相同。嘌呤和谷氨酸代谢途径在老年期和疾病状态下都会失调,对这两种途径进行基因靶向可部分挽救与野生型和突变型 tau 过表达相关的神经退行性表型。我们的研究结果支持用 "双击模型 "来解释与老年痴呆症相关的病理表现,即衰老和Tau/突触核蛋白驱动的代谢重编程事件相互配合,针对这两种事件的治疗可能是一种有效的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
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