Mazzola Jennifer L, Sirover Michael A
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Neurotoxicology. 2002 Oct;23(4-5):603-9. doi: 10.1016/s0161-813x(02)00062-1.
Recent evidence reveals that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is not simply a classical glycolytic protein of little interest. Instead, it is a multifunctional protein with diverse cytoplasmic, membrane and nuclear activities. Significantly, each activity is separate and distinctfrom its role in energy production. Its nuclear activities include its emerging role in apoptosis especially in neuronal cells. GAPDH translocates into the nucleus during programmed cell death. Introduction of antisense GAPDH sequences reduces apoptosis and prevents its nuclear translocation. Independent analyses demonstrate that GAPDH may be involved in the cellular phenotype of age-related neurodegenerative disorders. GAPDH binds uniquely in vitro to the beta-amyloid precursor protein (betaAPP), to huntingtin as well as to other triplet repeat neuronal disorder proteins. In Parkinson's disease (PD) cells, immunofluorescent data suggests the co-l localization of GAPDH and alpha-synuclein in Lewy bodies. Drugs used to treat PD bind specifically to GAPDH. Our recent findings (Mazzola and Sirover, 2001) demonstrate a subcellular reduction in GAPDH glycolytic activity in Alzheimer's disease (AD) and in Huntington's disease (HD) cells. The latter may be due to intracellular alteration of GAPDH structure (Mazzola and Sirover 2002). We discuss the hypothesis that the intracellularformation of GAPDH: neuronal protein complexes may represent an emerging cellular phenotype of neurodegenerative disorders. The cytoplasmic binding of neuronal proteins to GAPDH could affect energy production. Nuclear interactions could affect its apoptotic activity. Other functions of this multidimensional protein may also be inhibited. Experimental paradigms to test this hypothesis are considered.
最近的证据表明，甘油醛-3-磷酸脱氢酶（GAPDH）并非仅仅是一种不太受关注的经典糖酵解蛋白。相反，它是一种具有多种细胞质、膜和核活性的多功能蛋白。重要的是，每种活性都与其在能量产生中的作用分开且不同。其核活性包括其在细胞凋亡中，尤其是在神经元细胞中的新作用。在程序性细胞死亡期间，GAPDH会转运到细胞核中。引入反义GAPDH序列可减少细胞凋亡并阻止其核转运。独立分析表明，GAPDH可能参与与年龄相关的神经退行性疾病的细胞表型。GAPDH在体外独特地与β-淀粉样前体蛋白（βAPP）、亨廷顿蛋白以及其他三联体重复神经元疾病蛋白结合。在帕金森病（PD）细胞中，免疫荧光数据表明GAPDH和α-突触核蛋白在路易小体中共定位。用于治疗PD的药物特异性地与GAPDH结合。我们最近的研究结果（Mazzola和Sirover，2001年）表明，在阿尔茨海默病（AD）和亨廷顿病（HD）细胞中，GAPDH糖酵解活性在亚细胞水平降低。后者可能是由于GAPDH结构的细胞内改变（Mazzola和Sirover，2002年）。我们讨论了这样一种假说，即GAPDH：神经元蛋白复合物的细胞内形成可能代表神经退行性疾病一种新出现的细胞表型。神经元蛋白与GAPDH的细胞质结合可能会影响能量产生。核相互作用可能会影响其凋亡活性。这种多维蛋白的其他功能也可能受到抑制。考虑了检验这一假说的实验范式。
