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

• Published in: Life science alliance Vol. 7; no. 8; p. e202302535
• Main Authors: Pal, Arun, Grossmann, Dajana, Glaß, Hannes, Zimyanin, Vitaly, Günther, René, Catinozzi, Marica, Boeckers, Tobias M, Sterneckert, Jared, Storkebaum, Erik, Petri, Susanne, Wegner, Florian, Grill, Stephan W, Pan-Montojo, Francisco, Hermann, Andreas
• Format: Journal Article
• Language: English
• Published: United States Life Science Alliance LLC 01-08-2024
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Glycolates - metabolism; Glycolates - pharmacology; Humans; Lactic Acid - metabolism; Lysosomes - metabolism; Membrane Potential, Mitochondrial; Mitochondria - metabolism; Motor Neurons - metabolism; Protein Deglycase DJ-1 - genetics; Protein Deglycase DJ-1 - metabolism; RNA-Binding Protein FUS - genetics; RNA-Binding Protein FUS - metabolism; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202302535

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.