{"doi":"10.1101/2021.05.07.442949","title":"TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy","abstract":"ABSTRACT The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well-understood. Here, we investigated the influence of genotypes at TMEM106B , a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions in C9orf72 , a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)- allele homozygotes at the TMEM106B locus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions. C9orf72 expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting for C9orf72 expansion status did not affect the relationship between TMEM106B genotype and TDP-43 pathology. In order to elucidate the direction of causality for this association, we directly manipulated TMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown of TMEM106B , to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":225457,"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":0.9442,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":227427,"name":"John Robinson","orcid":"0000-0001-6858-2367","position":1,"is_corresponding":false},{"id":828268,"name":"Travis L. Unger","orcid":null,"position":2,"is_corresponding":false},{"id":827899,"name":"Marijan Posavi","orcid":"0000-0002-9590-2829","position":3,"is_corresponding":false},{"id":625500,"name":"Defne A. Amado","orcid":"0000-0001-6202-3900","position":4,"is_corresponding":false},{"id":495593,"name":"Lauren Elman","orcid":"0000-0003-4706-950X","position":5,"is_corresponding":false},{"id":58510,"name":"Murray Grossman","orcid":"0000-0002-7447-6218","position":6,"is_corresponding":false},{"id":230045,"name":"David A. Wolk","orcid":"0000-0002-3554-3481","position":7,"is_corresponding":false},{"id":107087,"name":"Edward B. Lee","orcid":"0000-0002-4589-1180","position":8,"is_corresponding":false},{"id":27603,"name":"Vivianna M. Van Deerlin","orcid":"0000-0002-7400-9097","position":9,"is_corresponding":false},{"id":260092,"name":"Sílvia Porta","orcid":"0000-0003-3667-4325","position":10,"is_corresponding":false},{"id":234364,"name":"Virginia Lee","orcid":null,"position":11,"is_corresponding":false},{"id":27606,"name":"John Q. Trojanowski","orcid":"0000-0002-9239-8794","position":12,"is_corresponding":false},{"id":76194,"name":"Alice S. Chen-Plotkin","orcid":"0000-0002-3387-2038","position":13,"is_corresponding":false},{"id":828267,"name":"Fei Mao","orcid":null,"position":0,"is_corresponding":true}],"reference_count":22,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:26.581453Z","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":[]}