Charcot Marie Tooth disease 4A - GDAP1-mediated redox-dependent interaction of mitochondria with the cytoskeleton

夏科玛丽图斯病 4A - GDAP1 介导的线粒体与细胞骨架的氧化还原依赖性相互作用

• 批准号: 517361457
• 负责人: Professor Dr. Axel Methner
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/517361457?language=en
• 关键词: Charcot; Marie; Tooth; disease; 4A

Charcot-Marie-Tooth disease 4A is an autosomal-recessive polyneuropathy caused by mutation of the mitochondrial protein GDAP1 (Ganglioside-induced differentiation associated protein 1). To date, no specific therapy exists to treat this devastating disease. We recently showed that patient-derived motoneurons carrying GDAP1 mutations display more tubular mitochondria, reduced mitochondrial Ca2+ levels, and an inhibited pyruvate dehydrogenase complex (PDC). The PDC dysfunction results in a rewired cellular metabolism characterized by glutamine dependence and increased reliance on fatty acid β-oxidation to supply acetyl-CoA for the tricarboxylic acid cycle. We identified Cofilin-1 (CFL1), an actin-polymerizing protein, and other proteins of the actin cytoskeleton as novel interaction partners of GDAP1. Disrupted GDAP1-CFL1 interaction leads to a reduced presence of filamentous actin in the proximity of mitochondria, precluding access of the major fission factor DRP1 to mitochondria. Thus, this novel interaction can explain the defective mitochondrial fission and the more tubular mitochondrial shape observed in various GDAP1 loss of function models but it is unclear if this also mediates the metabolic changes. As GDAP1 is a putative glutathione transferase, we hypothesize that GDAP1, upon interacting with proteins of the cytoskeleton, regulates actin dynamics via post-translational modification of cytoskeletal proteins. In line with this hypothesis, we have identified putative target proteins by redox proteomics; about a fourth of which overlap with the interactome. In this project, we will concentrate on a subset of these potential interactors and study if GDAP1 regulates their redox state and function and if this mediates the reduced mitochondrial Ca2+ levels and inhibition of the PDC. We also aim to identify diets and compounds that can revert the metabolic dysfunction instigated by GDAP1 loss of function and study their effect in (patient-derived) models of GDAP1 deficiency and in a recently established fly model. Together, this project aims to further characterize the pathophysiology of a human disease and identify potential drug targets for its treatment.

腓骨肌萎缩症4A是一种常染色体隐性遗传性多发性神经病，由线粒体蛋白GDAP 1（神经节苷脂诱导分化相关蛋白1）突变引起。迄今为止，还没有特定的疗法来治疗这种毁灭性的疾病。我们最近发现，携带GDAP 1突变的患者源性运动神经元显示更多的管状线粒体，线粒体Ca 2+水平降低，丙酮酸脱氢酶复合物（PDC）抑制。PDC功能障碍导致以谷氨酰胺依赖性为特征的重新连接的细胞代谢，并且增加了对脂肪酸β-氧化的依赖，以提供用于三羧酸循环的乙酰辅酶A。我们确定了Cofilin-1（CFL 1），肌动蛋白聚合蛋白，和其他蛋白的肌动蛋白细胞骨架作为新的相互作用的合作伙伴GDAP 1。破坏GDAP 1-CFL 1相互作用导致线粒体附近丝状肌动蛋白的存在减少，从而阻止主要裂变因子DRP 1进入线粒体。因此，这种新的相互作用可以解释在各种GDAP 1功能丧失模型中观察到的线粒体分裂缺陷和更多的管状线粒体形状，但尚不清楚这是否也介导了代谢变化。由于GDAP 1是一种假定的谷胱甘肽转移酶，我们假设GDAP 1与细胞骨架蛋白相互作用后，通过细胞骨架蛋白的翻译后修饰调节肌动蛋白动力学。根据这一假设，我们已经确定了推定的目标蛋白质的氧化还原蛋白质组学，其中约四分之一的重叠与相互作用。在本项目中，我们将集中研究这些潜在相互作用物的一个子集，并研究GDAP 1是否调节它们的氧化还原状态和功能，以及这是否介导线粒体Ca 2+水平降低和PDC抑制。我们还旨在确定可以逆转GDAP 1功能丧失引起的代谢功能障碍的饮食和化合物，并研究其在GDAP 1缺乏症（患者来源）模型和最近建立的苍蝇模型中的作用。总之，该项目旨在进一步表征人类疾病的病理生理学，并确定其治疗的潜在药物靶点。