{"doi":"10.1111/nan.12836","title":"Distinguishing post‐translational modifications in dominantly inherited frontotemporal dementias: FTLD‐TDP Type A ( <i>GRN</i> ) vs Type B ( <i>C9orf72</i> )","abstract":"AIMS: Frontotemporal dementias are neuropathologically characterised by frontotemporal lobar degeneration (FTLD). Intraneuronal inclusions of transactive response DNA-binding protein 43 kDa (TDP-43) are the defining pathological hallmark of approximately half of the FTLD cases, being referred to as FTLD-TDP. The classification of FTLD-TDP into five subtypes (Type A to Type E) is based on pathologic phenotypes; however, the molecular determinants underpinning the phenotypic heterogeneity of FTLD-TDP are not well known. It is currently undetermined whether TDP-43 post-translational modifications (PTMs) may be related to the phenotypic diversity of the FTLDs. Thus, the investigation of FTLD-TDP Type A and Type B, associated with GRN and C9orf72 mutations, becomes essential. METHODS: Immunohistochemistry was used to identify and map the intraneuronal inclusions. Sarkosyl-insoluble TDP-43 was extracted from brains of GRN and C9orf72 mutation carriers post-mortem and studied by Western blot analysis, immuno-electron microscopy and mass spectrometry. RESULTS: Filaments of TDP-43 were present in all FTLD-TDP preparations. PTM profiling identified multiple phosphorylated, N-terminal acetylated or otherwise modified residues, several of which have been identified for the first time as related to sarkosyl-insoluble TDP-43. Several PTMs were specific for either Type A or Type B, while others were identified in both types. CONCLUSIONS: The current results provide evidence that the intraneuronal inclusions in the two genetic diseases contain TDP-43 filaments. The discovery of novel, potentially type-specific TDP-43 PTMs emphasises the need to determine the mechanisms leading to filament formation and PTMs, and the necessity of exploring the validity and occupancy of PTMs in a prognostic/diagnostic setting.","journal":"Neuropathology and Applied Neurobiology","year":2022,"id":262183,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":437389,"name":"Emma H. Doud","orcid":"0000-0003-0049-0073","position":1,"is_corresponding":false},{"id":342602,"name":"Grace I. Hallinan","orcid":"0000-0001-6010-7449","position":2,"is_corresponding":false},{"id":342603,"name":"Holly J. Garringer","orcid":"0000-0002-1899-7676","position":3,"is_corresponding":false},{"id":495169,"name":"Max Jacobsen","orcid":"0000-0003-3344-898X","position":4,"is_corresponding":false},{"id":720770,"name":"Rose Richardson","orcid":"0000-0001-7164-0337","position":5,"is_corresponding":false},{"id":678025,"name":"Emanuele Buratti","orcid":"0000-0002-1356-9074","position":6,"is_corresponding":false},{"id":271115,"name":"Rubén Vidal","orcid":"0000-0002-5803-3871","position":7,"is_corresponding":false},{"id":268832,"name":"Bernardino Ghetti","orcid":"0000-0002-1842-8019","position":8,"is_corresponding":false},{"id":268829,"name":"Kathy L. Newell","orcid":"0000-0002-1648-7357","position":9,"is_corresponding":false},{"id":323724,"name":"Laura Cracco","orcid":"0000-0001-7693-0202","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T00:26:20.717229Z","pmid":"35836354","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":[]}