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Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.
- Source :
-
Life science alliance [Life Sci Alliance] 2024 May 17; Vol. 7 (8). Date of Electronic Publication: 2024 May 17 (Print Publication: 2024). - Publication Year :
- 2024
-
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.<br /> (© 2024 Pal et al.)
- Subjects :
- Humans
Membrane Potential, Mitochondrial
Motor Neurons metabolism
Lysosomes metabolism
Amyotrophic Lateral Sclerosis metabolism
Amyotrophic Lateral Sclerosis genetics
RNA-Binding Protein FUS metabolism
RNA-Binding Protein FUS genetics
Glycolates metabolism
Glycolates pharmacology
Mitochondria metabolism
Protein Deglycase DJ-1 metabolism
Protein Deglycase DJ-1 genetics
Lactic Acid metabolism
Superoxide Dismutase-1 metabolism
Superoxide Dismutase-1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2575-1077
- Volume :
- 7
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Life science alliance
- Publication Type :
- Academic Journal
- Accession number :
- 38760174
- Full Text :
- https://doi.org/10.26508/lsa.202302535