{"doi":"10.5772/intechopen.92696","title":"The Role of TDP-43 in Genome Repair and beyond in Amyotrophic Lateral Sclerosis","abstract":"The pathology of the RNA-/DNA-binding protein TDP-43, first implicated a decade ago in the motor neuron disease amyotrophic lateral sclerosis (ALS), has been subsequently linked to a wide spectrum of neurodegenerative diseases, including frontotemporal dementia (FTD), Alzheimer's disease (AD), and related dementia-associated disorders. ALS, also known as Lou Gehrig's disease, is a progressive, degenerative motor neuron disorder, characterized by a diverse etiopathology. TDP-43 pathology, mediated by a combination of several mutations in the TARDBP gene and stress factors, has been linked to more than 97% of ALS patients. We recently identified, for the first time, the critical involvement of TDP-43 in neuronal genome maintenance and the repair of DNA double-strand breaks (DSBs). Our studies showed that TDP-43 regulates the DNA break-sealing activities of the XRCC4-DNA Ligase 4 (LIG4) complex in DSB repair, suggesting that loss of genomic integrity in TDP-43-associated neurodegeneration may be amenable to a DNA repair-based intervention. In this chapter, we discuss the broader aspects of TDP-43 toxicityinduced pathomechanisms, including the emerging role of TDP-43 in neuronal DSB repair and its synergistic genotoxic effects with other neurodegeneration-associated etiologies that contribute significantly to neuronal dysfunction. We also discuss potential future perspectives and underscore how unraveling the molecular basis and implications of TDP-43-induced genome instability in ALS could guide the development of neuroprotective therapies.","journal":"IntechOpen eBooks","year":2020,"id":118127,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9616,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":294863,"name":"Muralidhar L. Hegde","orcid":"0000-0001-7333-8123","position":1,"is_corresponding":false},{"id":475094,"name":"Joy Mitra","orcid":"0000-0002-5985-0582","position":0,"is_corresponding":true}],"reference_count":160,"raw_metadata":null,"created_at":"2026-07-18T23:13:58.531532Z","pmid":null,"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":[]}