Hollán S, Vécsei L, Karg E, Németh I, Horanyi M, Inselt-Kovács M, Farkas T
Institut National de Transfusion Sanguine, Budapest, Hongrie.
C R Seances Soc Biol Fil. 1998;192(5):929-45.
This study was devoted to the continued search for an explanation of the neurodegeneration found in a severely TPI deficient Hungarian patient whose brother with genomically completely identical TPI defect was completely free of neurological disorders. The changes found in the molecular species composition of the major PL subclasses and the decrease in PE plasmalogens explain the earlier round increase in membrane fluidity interfering thereby with the physiological function of membrane enzymes, receptors, signal transduction, protein-protein interactions and vesicle fusion. Plasmalogens have also the capacity to protect against oxidative stress, that is deemed to contribute to neurodegenerative processes. The presence of chronic oxidative stress was well reflected in the decreased levels of GSH and alpha-tocopherol in the affected brothers. Decrease in plasmalogens have been described recently in Zellweger's syndrome, in other peroxisomal neurodegenerative disorders, in demyelinating processes and in Alzheimer's disease. The brain in normal individuals is highly enriched in plasmalogens. The pathological decrease found in TPI deficient lymphocytes will presumably be more pronounced in excitatory tissues. The recently described role of expanding nucleotide triplets in the development of neurodegeneration is suggested to result through the selective binding via their polyglutamine repeats to GAPDH. The role of GAPDH in TPI deficiency may be of crucial help in the elucidation of the development of neurodegeneration, since the enzymatic defect of TPI can be partially bypassed by means of the HMP shunt which generates GAP via GAPDH without the participation of TPI. Considering the results found in TPI deficiency in comparison to the new literary findings in different neurodegenerative diseases the following pathomechanism may be proposed. The protein products of the defective genes due to their abnormal steric structure bind GAPDH in a different manner or in differing quantity than their normal counterparts. The PL composition and the resulting differences in the biophysical properties of the cell membranes have crucial impact on these protein-protein interactions and on the activity of enzymes and membrane transport functions. The plasmalogen decrease impairs the protection against oxidative stress with consecutive worsening of the neurodegenerative process. The final common pathway to neuronal death leads through destabilization of intracellular Ca2+ homeostasis via elevation of intracellular Ca2+ to apoptosis. The most important conclusion is that lipids are not an inert environment of membrane proteins. Unravelling of the pathogenesis of neurodegeneration needs more concerted investigation of the interactions between genetic changes with biophysical and biochemical cell membrane lipid alterations.
本研究致力于继续探寻一名严重缺乏TPI的匈牙利患者出现神经退行性变的原因，该患者的哥哥虽然基因组中TPI缺陷完全相同，但却未出现任何神经紊乱症状。在主要磷脂亚类分子种类组成中发现的变化以及缩醛磷脂（PE）含量的降低，解释了早期膜流动性的增加，进而干扰了膜酶、受体、信号转导、蛋白质 - 蛋白质相互作用以及囊泡融合的生理功能。缩醛磷脂还具有抵御氧化应激的能力，而氧化应激被认为与神经退行性变过程有关。受影响兄弟体内谷胱甘肽（GSH）和α - 生育酚水平的降低充分反映了慢性氧化应激的存在。最近在脑肝肾综合征、其他过氧化物酶体神经退行性疾病、脱髓鞘过程以及阿尔茨海默病中都发现了缩醛磷脂含量的降低。正常个体的大脑中富含缩醛磷脂。在TPI缺乏的淋巴细胞中发现的病理性降低，在兴奋性组织中可能会更加明显。最近描述的扩展核苷酸三联体在神经退行性变发展中的作用，被认为是通过其多聚谷氨酰胺重复序列与甘油醛 - 3 - 磷酸脱氢酶（GAPDH）的选择性结合而产生的。GAPDH在TPI缺乏中的作用，可能对阐明神经退行性变的发展具有至关重要的帮助，因为TPI的酶缺陷可以通过磷酸戊糖途径（HMP）部分绕过，该途径通过GAPDH产生GAP，而无需TPI的参与。结合TPI缺乏的研究结果以及不同神经退行性疾病的新文献发现，可能会提出以下发病机制。由于其异常的空间结构，缺陷基因的蛋白质产物以与正常对应物不同的方式或不同数量结合GAPDH。磷脂组成以及由此导致的细胞膜生物物理性质差异，对这些蛋白质 - 蛋白质相互作用以及酶活性和膜转运功能具有至关重要的影响。缩醛磷脂含量降低会损害对氧化应激的保护作用，进而导致神经退行性变过程的持续恶化。神经元死亡的最终共同途径是通过细胞内Ca2 + 稳态的破坏，即细胞内Ca2 + 升高导致细胞凋亡。最重要的结论是，脂质并非膜蛋白的惰性环境。阐明神经退行性变的发病机制需要更协调一致地研究基因变化与生物物理和生化细胞膜脂质改变之间的相互作用。
