Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases

Topic: Brain proteins, microglia and lab models

TDP-43 proteinopathy is central to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 plays a key role in DNA double-strand break repair (DSBR), though the underlying mechanisms remain unclear. Here, we demonstrate that ALS patients’ brains exhibit persistent DNA damage within transcribed genes. Mechanistically, activity of polynucleotide kinase 3′-phosphatase (PNKP), an essential DNA end-processing enzyme required for DSBR in transcribed genes, is impaired in ALS brains and TDP-43–depleted cells. Such defect stems from reduced levels of PNKP-interacting enzyme phosphofructo-2- kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and its metabolic product fructose-2,6- bisphosphate (F2,6BP), an essential cofactor of PNKP. F2,6BP supplementation reduces cytosolic aggregation of phosphorylated and polyubiquitinated TDP-43 in patient-derived induced neurons, rescues PNKP activity in ALS/FTD brain extracts, and improves motor deficits in Drosophila TDP-43 model. Together, these findings reveal a critical link between metabolic dysregulation and genomic instability in TDP-43 pathology-associated motor neuron diseases, and underscore therapeutic potential of F2,6BP. TDP-43 pathology in ALS and FTD disrupts DNA repair in transcribed genes through metabolic dysregulation. This study identifies a glycolytic metabolite that restores genome repair, reduces TDP-43 toxicity, and improves disease-relevant phenotypes.

Key findings

• Together, these findings reveal a critical link between metabolic dysregulation and genomic instability in TDP-43 pathology-associated motor neuron diseases, and underscore therapeutic potential of F2,6BP.

Why it matters

The study found that TDP-43 pathology impairs DNA repair in motor neuron diseases through reduced levels of a metabolite called F2,6BP, and that adding F2,6BP reduced TDP-43 aggregates in patient-derived neurons and improved motor deficits in a fruit fly model. This is early laboratory work that points to a possible therapeutic target, not a proven treatment.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s42003-026-09787-5
• PubMed: 41807755
• Original source →
• Free full text: Communications Biology →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{chakraborty2026-41807755,
  author  = {Chakraborty, Anirban and Mitra, Joy and Malojirao, Vikas H. and Kodavati, Manohar M. and Mandal, Santi M. and Gill, Satkarjeet K. and Sreenivasmurthy, Sravan Gopalkrishnashetty and Vasquez, Velmarini and others},
  title   = {{Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases}},
  journal = {Communications Biology},
  year    = {2026},
  doi     = {10.1038/s42003-026-09787-5},
  pmid    = {41807755},
  url     = {https://doi.org/10.1038/s42003-026-09787-5}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Structure of pathological TDP-43 filaments from ALS with FTLD Nature · 2021-12-08 · usefulness score 58/100 · Lewy body dementia
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• A Drosophila model for TDP-43 proteinopathy Proceedings of the National Academy of Sciences of the United States of America · 2010-01-26 · usefulness score 49/100 · Brain tissue and pathology
• Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence Acta Neuropathologica Communications · 2025-03-08 · usefulness score 44/100 · Brain tissue and pathology

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