Role of DJ1 in mitochondrial biogenergetics and neuronal metabolism

摘要 乔纳斯，俄亥俄州 家族性帕金森病(PD)蛋白DJ-1突变与线粒体缺陷和 早发性帕金森病，但确切的发病机制尚不清楚。我们发现DJ-1和DJ-1的突变 DJ-1基因敲除增加线粒体解偶联，阻碍心肌细胞伸展和分支 多巴胺能神经元突起。解偶联与ATP合酶异常有关 效率和化学计量比。ATP合酶的变化也与线粒体有关 形态变化，包括冠状突数、线粒体长度和 线粒体生物发生。新的蛋白质合成对修复和维持多巴胺能至关重要 纹状体的终末和正常的多巴胺释放能力。新蛋白的激活 合成是对生长因子或神经元刺激等信号的反应，但我们 假设当ATP合成酶的化学计量比达到时，新的蛋白质合成不会发生 是不正常的。与此一致的是，我们发现患者细胞中的蛋白质合成水平非常低。 在DJ-1 KO小鼠神经元中。DJ-1与三磷酸腺苷合成酶β亚基和三磷酸腺苷合成酶β结合 亚基mR-NA。因此，我们假设生长和分枝减少的机制 DJ-1缺陷的多巴胺能神经元与缺乏DJ-1靶向，线粒体- 神经元生长、修复和多巴胺能可塑性所需的受调控的mRNAs 细胞。如果我们能够在空间和空间上恢复DJ-1下游蛋白质合成的正常速度 以时间精确的方式，我们假设我们将减缓DJ-1的神经末梢退化 突变患者并保持多巴胺释放能力。为了与此保持一致，我们现在有 通过过表达三磷酸腺苷合成酶β亚单位来恢复患者细胞的蛋白质合成速率。我们 现在计划确定我们是否可以挽救DJ-1的低蛋白质合成率和神经元生长 表达突变型DJ-1的神经元和DJ-1 KO动物体内的KO神经元。我们会这么做的 通过腺病毒(病毒)递送在神经元中过表达三磷酸腺苷合成酶β亚单位。在体内，我们将 用低c亚基与DJ-1 KO小鼠杂交恢复线粒体的正常偶联 利奇老鼠。我们将通过跨越DJ-DJ-来恢复体内正常的ATP合成酶化学计量比 1 KO小鼠与小鼠过表达三磷酸腺苷合成酶β亚单位。我们希望保存 纹状体中的神经元终末和防止小鼠功能障碍运动的开始。 我们的观察表明，ATP合成酶复合体化学计量学、蛋白质 合成率和PD。我们的计划包括一项前景看好的新战略，以开发治疗 帕金森病患者。

Abstract Jonas, EA Familial Parkinson’s disease (PD) protein DJ-1 mutations are linked to mitochondrial deficits and early onset PD but the exact mechanisms are unclear. We have found that mutations in DJ-1 and DJ-1 knock out increase mitochondrial uncoupling and hamper extension and branching of dopaminergic neuronal processes. The uncoupling is associated with abnormal ATP synthase efficiency and stoichiometry. The changes in ATP synthase are also associated with mitochondrial morphological changes including changes in cristae number, mitochondrial length and mitochondrial biogenesis. New protein synthesis is crucial to repair and maintain dopaminergic endings in the striatum and for normal dopamine release capacity. The activation of new protein synthesis is in response to cues such as growth factors or neuronal stimulation, but we hypothesize that new protein synthesis fails to occur when the stoichiometry of the ATP synthase is abnormal. In keeping with this, we find that protein synthesis levels are very low in patient cells and in DJ-1 KO mouse neurons. DJ-1 is bound to ATP synthase β subunit and ATP synthase β subunit mRNA. We therefore hypothesize that the mechanism of decreased growth and branching of DJ-1 deficient dopaminergic neurons is related to a lack of DJ-1 targeted, mitochondrially- regulated, mRNAs that are required for neuronal growth, repair and plasticity of dopaminergic cells. If we can restore the normal rate of protein synthesis downstream of DJ-1 in a spatially and temporally precise manner, we hypothesize we will slow neuronal ending degradation in DJ-1 mutant patients and preserve dopamine release capability. In keeping with this, we have now restored protein synthesis rates in patient cells by overexpression of ATP synthase β subunit. We now plan to determine if we can rescue low protein synthesis rates and neuronal growth in DJ-1 KO neurons, in neurons expressing mutant DJ-1 and in vivo in DJ-1 KO animals. We will do this by overexpression of ATP synthase β subunit by AAV (viral) delivery in neurons. In vivo, we will restore the normal coupling of mitochondria by crossing the DJ-1 KO mice with a low c-subunit leak KI mouse. We will restore the normal ATP synthase stoichiometry in vivo by crossing the DJ- 1 KO mouse with a mouse overexpressing ATP synthase β subunit. We hope to preserve neuronal endings in the striatum and prevent the onset of dysfunctional movement in the mice. Our observations suggest a connection between ATP synthase complex stoichiometry, protein synthesis rates and PD. Our plan comprises a promising new strategy to develop therapies for PD patients.