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The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models

机译：糖酵解酶GPI是帕金森模型中多巴胺能神经变性的功能保守修饰因子

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Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.
机译：神经退行性疾病在我们的老龄化社会中代表着越来越重的负担，但是影响发作和进展的潜在代谢因素仍然不清楚。受损的IGF-1 /胰岛素样信号传导（IIS）与寿命延长之间的关系为研究代谢与年龄相关性神经变性的界面提供了机会。利用秀丽隐杆线虫中已建立的DAF-2 / IIS信号转导成分的数据集，我们在蠕虫中进行了系统的RNAi筛选，以选择与daf-2相关的α-突触核蛋白错折叠和多巴胺能神经变性的遗传修饰剂，这是帕金森氏病的两个临床标志。该策略的结果是鉴定了葡萄糖代谢中的一种酶GPI-1 / GPI，它是由daf-2调节的修饰物，其作用独立于下游细胞保护性转录因子DAF-16 / FOXO来调节神经保护作用。随后的使用果蝇和小鼠原代神经元文化的机制分析进一步证实了GPI神经保护免受α-突触核蛋白蛋白毒性的保守性质。总的来说，这些结果支持葡萄糖代谢作为蛋白稳态和神经变性相交处的保守功能节点。

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