Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany.
Dresden High Magnetic Field Laboratory (HLD-EMFL), Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
Life Sci Alliance. 2024 May 17;7(8). doi: 10.26508/lsa.202302535. Print 2024 Aug.
Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of (SOD1)- and in particular (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.
肌萎缩侧索硬化症（ALS）会导致患者在 2-5 年内死亡。目前，可用的药物只能略微延长患者的生存时间。我们通过揭示与帕金森病相关的糖氧酶 DJ-1 的潜在产物——乙醛酸（GA）和 D-乳酸（DL）——在 SOD1-和 FUS-ALS 中的病理生理学中呈现出的新见解，为 ALS 的病理生理学提供了新的见解。GA/DL 的联合而非单一治疗恢复了 FUS 和 SOD1-ALS 患者来源运动神经元（MNs）中线粒体和溶酶体的轴突细胞器表型。这不仅伴随着线粒体膜电位的恢复，甚至还依赖于它。尽管 TDP43 患者来源的 MNs 也存在轴突运输缺陷，但它们没有表现出线粒体去极化，也没有对 GA/DL 治疗产生反应。GA 和 DL 还恢复了 FUS 的细胞质定位错误，并将 FUS 募集到 DNA 损伤部位，最近的研究表明，这是 FUS-ALS 中线粒体表型的上游事件。虽然这些数据表明需要针对个体（基因）的特定治疗策略进行分层，但也表明在不同以线粒体去极化为特征的神经退行性疾病中存在共同的治疗靶点。
