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

IF 8 1区 医学 Q1 CELL 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.

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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。
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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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