The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models.
The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models.
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DOI：
10.1016/j.cmet.2014.04.017
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发表时间：
2014-07-01
期刊：
影响因子：
29
通讯作者：
Caldwell GA
中科院分区：
文献类型：
--
作者：
Knight AL;Yan X;Hamamichi S;Ajjuri RR;Mazzulli JR;Zhang MW;Daigle JG;Zhang S;Borom AR;Roberts LR;Lee SK;DeLeon SM;Viollet-Djelassi C;Krainc D;O'Donnell JM;Caldwell KA;Caldwell GA
神经退行性疾病在我们的老龄化社会中代表了日益增加的负担，但影响发病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）和寿命延长之间的关系代表了一个机会，以研究代谢与年龄相关的神经退行性变的接口。使用秀丽隐杆线虫中已建立的daf-2/IIS信号传导组分的数据集，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-突触核蛋白错误折叠和多巴胺能神经变性的遗传修饰剂，这是帕金森病的两个临床标志。该策略的结果是鉴定出gpi-1/GPI（一种葡萄糖代谢酶）作为daf-2调节的修饰剂，其作用独立于下游细胞保护转录因子DAF-16/FOXO，以调节神经保护。随后使用果蝇和小鼠原代神经元培养物的机制分析进一步验证了GPI神经保护免受α-突触核蛋白蛋白毒性的保守性。总的来说，这些结果支持葡萄糖代谢作为蛋白质稳态和神经变性交叉点的保守功能节点。
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 datasets of established daf-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-assoicated 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.
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DOI：
10.1016/s0167-4838(00)00075-3
发表时间：
2000-07-14
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY
影响因子：
--
作者：
Haga, A;Niinaka, Y;Raz, A
通讯作者：
Raz, A
影响因子：
4.8
作者：
McElwee, JJ;Schuster, E;Gems, D
通讯作者：
Gems, D
DOI：
10.1073/pnas.0711018105
发表时间：
2008-01-15
影响因子：
11.1
作者：
Hamamichi, Shusei;Rivas, Renee N.;Caldwell, Guy A.
通讯作者：
Caldwell, Guy A.
DOI：
10.1073/pnas.0307697101
发表时间：
2004-04-27
影响因子：
11.1
作者：
Nollen, EAA;Garcia, SM;Plasterk, RHA
通讯作者：
Plasterk, RHA
影响因子：
7
作者：
Halaschek-Wiener, J;Khattra, JS;Riddle, DL
通讯作者：
Riddle, DL