Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.
Life Sci Alliance
; 7(8)2024 Aug.
Article
in En
| MEDLINE
| ID: mdl-38760174
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Lactic Acid
/
RNA-Binding Protein FUS
/
Protein Deglycase DJ-1
/
Superoxide Dismutase-1
/
Glycolates
/
Amyotrophic Lateral Sclerosis
/
Mitochondria
Limits:
Humans
Language:
En
Journal:
Life Sci Alliance
Year:
2024
Type:
Article
Affiliation country:
Germany