维生素B3对PINK1突变帕金森病转基因果蝇的作用及其与糖酵解的关系

The damage of NADH dehydrogenase, which is another name of mitochondrial respiratory chain complex I (CI) ,has been considered to be an important cause in the Parkinson's disease (PD) Pathogenesis,however,large-scale clinical trials have been verified the fact that enhancing the activity of CI by co-enzyme Q was not effective in treating PD patients.We had proved that the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression was decreased obviously in dopamine neurons of PD transgenic Drosophila PTEN induced putative kinase 1 (PINK1) mutants . GAPDH is the key enzyme in glycolysis , which function is turned the oxidation state of NAD+ to the reduction state of NADH during the Oxidative Respiratory Chain . Vitamin B3 ,whcih has an important role in the co-enzyme I , not only can induce the expression of GAPDH (NAM vitamin B3), was also found only in neurons of NAD+ synthesis of co-enzyme I precursor (NR vitamin B3).In this study, we will study further that vitamin B3 (NAM or NR) whether could suppress the degeneration of dopamine neuron in,PINK1 mutant PD transgenic Drosophila and make sure the vitamin B3 protective effect relating to GAPDH expression and NAD+ synthesis leading to enhanced glycolysis function ; and further study whether vitamin B3 combined with co-enzyme Q has synergistic neuroprotective effect on PINK1 mutant PD transgenic flies, to determine whether PD exist at the same time the glycolysis and CI dysfunction, and provide a theoretical basis for the exploration of PD drugs.

NADH-辅酶Q还原酶即线粒体氧化呼吸链复合物I（CI）损害一直被认为是帕金森病(PD)发病的重要原因，而大规模临床试验证实用辅酶Q增强CI活性并不能有效治疗PD。我们在预实验中发现，PINK1突变PD转基因果蝇多巴胺神经元中3磷酸甘油醛脱氢酶（GAPDH）表达显著降低。GAPDH为糖酵解关键酶，其作用是将氧化呼吸所产生的辅酶I氧化态NAD+还原成还原态NADH。维生素B3是辅酶I的重要组成部分，其不但可诱导GAPDH表达，还是迄今发现的唯一能在神经元中合成NAD+的辅酶I前体。在本课题中，我们将研究维生素B3能否抑制PD转基因果蝇多巴胺神经元变性，明确其神经保护作用是否与GAPDH表达以及NAD+合成增多导致的糖酵解功能增强有关；并进一步研究维生素B3联合辅酶Q是否对PD转基因果蝇具有协同神经保护作用，明确PD是否同时存在糖酵解和CI功能障碍，为探索PD治疗药物提供实验依据。

NADH-辅酶Q还原酶即线粒体氧化呼吸链复合物I（CI）损害一直被认为是帕金森病(PD)发病的重要原因，而大规模临床试验证实用辅酶Q增强CI活性并不能有效治疗PD。我们在预实验中发现，PINK1突变PD转基因果蝇多巴胺神经元中3磷酸甘油醛脱氢酶（GAPDH）表达显著降低。GAPDH为糖酵解关键酶，其作用是将氧化呼吸所产生的辅酶I氧化态NAD+还原成还原态NADH。维生素B3是辅酶I的重要组成部分，其不但可诱导GAPDH表达，还是迄今发现的唯一能在神经元中合成NAD+的辅酶I前体。在本课题中，我们发现维生素B3可以改善PD模型果蝇的表型，抑制其DA神经元变性，同时挽救线粒体形态，提高ComplexI的呼吸活性，而敲低GAPDH2基因后，以上保护现象明显减弱，说明维生素B3 通过提高GAPDH 表达、增加糖酵解活性，从而挽救PINK1 突变PD 转基因果蝇，为探索PD治疗药物提供实验依据。.