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

Life Sci Alliance. 2024 May 17;7(8):e202302535. 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 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.

MeSH terms

  • 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


  • glycolic acid
  • FUS protein, human
  • SOD1 protein, human
  • PARK7 protein, human