Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.

IF 3.3 2区 生物学 Q1 BIOLOGY
Life Science Alliance Pub Date : 2024-05-17 Print Date: 2024-08-01 DOI:10.26508/lsa.202302535
Arun Pal, Dajana Grossmann, Hannes Glaß, Vitaly Zimyanin, René Günther, Marica Catinozzi, Tobias M Boeckers, Jared Sterneckert, Erik Storkebaum, Susanne Petri, Florian Wegner, Stephan W Grill, Francisco Pan-Montojo, Andreas Hermann
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引用次数: 0

Abstract

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 Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (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.

甘醇酸和D-乳酸--DJ-1的潜在产物--可恢复FUS-ALS和SOD1-ALS的神经退行性变。
肌萎缩性脊髓侧索硬化症(ALS)会导致患者在 2-5 年内死亡。我们对超氧化物歧化酶1(SOD1)--尤其是融合肉瘤(FUS)--渐冻人症的病理生理学提出了新的见解,揭示了乙醇酸(GA)和D-乳酸(DL)--两者都是与帕金森病相关的乙醛酸化酶DJ-1的假定产物--的所谓核心作用。在 FUS- 和 SOD1-ALS 患者衍生的运动神经元(MNs)中,GA/DL 的联合而非单一处理可恢复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,甚至还依赖于线粒体膜电位的恢复。尽管 TDP43 患者衍生的运动神经元也存在轴突运输缺陷,但它们的线粒体并没有去极化,对 GA/DL 处理也没有反应。GA和DL还能恢复FUS的胞质误定位和FUS在DNA损伤位点的招募,最近有报道称这是FUS-ALS线粒体表型的上游。这些数据表明有必要进行个体化(基因)特异性治疗分层,同时也提示了以线粒体去极化为特征的不同神经退行性疾病的共同治疗靶点。
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来源期刊
Life Science Alliance
Life Science Alliance Agricultural and Biological Sciences-Plant Science
CiteScore
5.80
自引率
2.30%
发文量
241
审稿时长
10 weeks
期刊介绍: Life Science Alliance is a global, open-access, editorially independent, and peer-reviewed journal launched by an alliance of EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press. Life Science Alliance is committed to rapid, fair, and transparent publication of valuable research from across all areas in the life sciences.
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