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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月10日

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  • Anirban Chakraborty,
  • Joy Mitra,
  • Vikas H. Malojirao,
  • Manohar Kodavati,
  • Santi M. Mandal,
  • Satkarjeet K. Gill,
  • Sravan Gopalkrishnashetty Sreenivasmurthy,
  • Velmarini Vasquez,
  • Mikita Mankevich,
  • Ludo Van Den Bosch,
  • Ralph M. Garruto,
  • Ian Robey,
  • Balaji Krishnan,
  • Gourisankar Ghosh,
  • Muralidhar L. Hegde,
  • Tapas Hazra

摘要

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.