Mazzola J L, Sirover M A
Department of Pharmacology, Temple University, School of Medicine, Philadelphia 19140, USA.
J Neurochem. 2001 Jan;76(2):442-9. doi: 10.1046/j.1471-4159.2001.00033.x.
New functions have been identified for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) including its role in neurodegenerative disease and in apoptosis. GAPDH binds specifically to proteins implicated in the pathogenesis of a variety of neurodegenerative disorders including the beta-amyloid precursor protein and the huntingtin protein. However, the pathophysiological significance of such interactions is unknown. In accordance with published data, our initial results indicated there was no measurable difference in GAPDH glycolytic activity in crude whole-cell sonicates of Alzheimer's and Huntington's disease fibroblasts. However, subcellular-specific GAPDH-protein interactions resulting in diminution of GAPDH glycolytic activity may be disrupted or masked in whole-cell preparations. For that reason, we examined GAPDH glycolytic activity as well as GAPDH-protein distribution as a function of its subcellular localization in 12 separate cell strains. We now report evidence of an impairment of GAPDH glycolytic function in Alzheimer's and Huntington's disease subcellular fractions despite unchanged gene expression. In the postnuclear fraction, GAPDH was 27% less glycolytically active in Alzheimer's cells as compared with age-matched controls. In the nuclear fraction, deficits of 27% and 33% in GAPDH function were observed in Alzheimer's and Huntington's disease, respectively. This evidence supports a functional role for GAPDH in neurodegenerative diseases. The possibility is considered that GAPDH:neuronal protein interaction may affect its functional diversity including energy production and as well as its role in apoptosis.
已确定甘油醛-3-磷酸脱氢酶（GAPDH）具有新功能，包括其在神经退行性疾病和细胞凋亡中的作用。GAPDH能特异性结合与多种神经退行性疾病发病机制相关的蛋白质，包括β-淀粉样前体蛋白和亨廷顿蛋白。然而，这种相互作用的病理生理学意义尚不清楚。根据已发表的数据，我们的初步结果表明，阿尔茨海默病和亨廷顿病成纤维细胞的全细胞粗提物超声裂解液中，GAPDH的糖酵解活性没有可测量的差异。然而，导致GAPDH糖酵解活性降低的亚细胞特异性GAPDH-蛋白质相互作用在全细胞制剂中可能会被破坏或掩盖。因此，我们在12个不同的细胞系中，研究了GAPDH的糖酵解活性以及GAPDH-蛋白质分布与其亚细胞定位的关系。我们现在报告证据表明，尽管基因表达未改变，但阿尔茨海默病和亨廷顿病亚细胞组分中GAPDH的糖酵解功能受损。在核后组分中，与年龄匹配的对照组相比，阿尔茨海默病细胞中GAPDH的糖酵解活性降低了27%。在细胞核组分中，分别在阿尔茨海默病和亨廷顿病中观察到GAPDH功能缺失27%和33%。这一证据支持了GAPDH在神经退行性疾病中的功能作用。人们认为GAPDH与神经元蛋白质的相互作用可能会影响其功能多样性，包括能量产生以及其在细胞凋亡中的作用。
