{"doi":"10.1101/2024.11.13.623464","title":"Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases","abstract":"TAR DNA-binding protein 43 (TDP-43) proteinopathy plays a critical role in neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). In our recent discovery, we identified that TDP-43 plays an essential role in DNA double-strand break (DSB) repair via the non-homologous end joining (NHEJ) pathway. Here, we found persistent DNA damage in the brains of ALS/FTD patients, primarily in the transcribed regions of the genome. We further investigated the underlying mechanism and found that polynucleotide kinase 3'-phosphatase (PNKP) activity was severely impaired in the nuclear extracts of both patient brains and TDP-43-depleted cells. PNKP is a key player in DSB repair within the transcribed genome, where its 3'-P termini processing activity is crucial for preventing persistent DNA damage and neuronal death. The inactivation of PNKP in ALS/FTD was due to reduced levels of its interacting partner, phosphofructo-2-kinase fructose 2,6 bisphosphatase (PFKFB3), and its biosynthetic product, fructose-2,6-bisphosphate (F2,6BP), an allosteric modulator of glycolysis. Recent work from our group has shown that F2,6BP acts as a positive modulator of PNKP activity in vivo. Notably, exogenous supplementation with F2,6BP restored PNKP activity in nuclear extracts from ALS/FTD brain samples and patient-derived induced pluripotent stem (iPS) cells harboring pathological mutations. Furthermore, we demonstrate that supplementation of F2,6BP restores genome integrity and partially rescues motor phenotype in a Drosophila model of ALS. Our findings underscore the possibility of exploring the therapeutic potential of F2,6BP or its analogs in TDP-43 pathology-associated motor neuron diseases.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":506272,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":475094,"name":"Joy Mitra","orcid":"0000-0002-5985-0582","position":1,"is_corresponding":false},{"id":1239073,"name":"Vikas H. Malojirao","orcid":null,"position":2,"is_corresponding":false},{"id":1208921,"name":"Manohar Kodavati","orcid":"0000-0001-5827-6964","position":3,"is_corresponding":false},{"id":646524,"name":"Santi M. Mandal","orcid":"0000-0002-0119-7138","position":4,"is_corresponding":false},{"id":1357178,"name":"S.S. Gill","orcid":"0000-0003-2256-6737","position":5,"is_corresponding":false},{"id":1231891,"name":"Sravan Gopalkrishnashetty Sreenivasmurthy","orcid":null,"position":6,"is_corresponding":false},{"id":1224102,"name":"Velmarini Vasquez","orcid":"0000-0001-6312-1799","position":7,"is_corresponding":false},{"id":1357530,"name":"Mikita Mankevich","orcid":null,"position":8,"is_corresponding":false},{"id":237403,"name":"Ludo Van Den Bosch","orcid":"0000-0003-0104-4067","position":9,"is_corresponding":false},{"id":1224103,"name":"Ralph M. Garruto","orcid":"0000-0003-4985-8190","position":10,"is_corresponding":false},{"id":1357531,"name":"Ian Robey","orcid":null,"position":11,"is_corresponding":false},{"id":744899,"name":"Balaji Krishnan","orcid":"0000-0003-2074-4165","position":12,"is_corresponding":false},{"id":304202,"name":"Gourisankar Ghosh","orcid":"0000-0001-6311-7351","position":13,"is_corresponding":false},{"id":294863,"name":"Muralidhar L. Hegde","orcid":"0000-0001-7333-8123","position":14,"is_corresponding":false},{"id":348403,"name":"Tapas K. Hazra","orcid":"0000-0002-4587-687X","position":15,"is_corresponding":false},{"id":348399,"name":"Anirban Chakraborty","orcid":"0000-0002-6558-0179","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T02:10:50.984927Z","pmid":"39990425","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}