Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases - PubMed
12 hours ago
- #TDP-43
- #DNA repair
- #ALS
- TDP-43 proteinopathy is central to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- ALS patients' brains show persistent DNA damage within transcribed genes.
- Polynucleotide kinase 3'-phosphatase (PNKP) activity is impaired in ALS brains and TDP-43-depleted cells.
- The impairment is due to reduced levels of PFKFB3 and its metabolic product fructose-2,6-bisphosphate (F2,6BP).
- F2,6BP supplementation reduces TDP-43 aggregation, rescues PNKP activity, and improves motor deficits in a Drosophila model.
- The findings highlight a link between metabolic dysregulation and genomic instability in TDP-43 pathology-associated motor neuron diseases.
- F2,6BP shows therapeutic potential for ALS and FTD.