{"doi":"10.1101/2022.06.10.22276260","title":"Conserved gene signatures shared among <i>MAPT</i> mutations reveal defects in calcium signaling","abstract":"Abstract More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau. To do this, we analyzed genes differentially expressed in induced pluripotent stem cell (iPSC)–derived neurons that represent the three major categories of MAPT mutations: splicing (IVS10+16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. Here, we identified 275 genes that were commonly differentially expressed in MAPT IVS10+16, p.P301L, and p.R406W neurons. These genes were enriched in synaptic and endolysosomal pathways and neuronal development and were also altered in the presence of tau aggregation in a mouse model of tauopathy. The MAPT mutations commonly led to changes in genes and pathways sensitive to disruptions in calcium homeostasis. One of these genes, CALB1 , plays a role in calcium dysregulation and is targeted by several FDA- approved drugs used to treat neurological symptoms. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from progressive supranuclear palsy patients, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-derived neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and endolysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.","journal":"medRxiv","year":2022,"id":303595,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"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":626240,"name":"Sidhartha Mahali","orcid":"0000-0001-5750-7118","position":1,"is_corresponding":false},{"id":453600,"name":"Abhirami K. Iyer","orcid":"0000-0003-1914-6045","position":2,"is_corresponding":false},{"id":895484,"name":"Rita Martinez","orcid":null,"position":3,"is_corresponding":false},{"id":27622,"name":"John Budde","orcid":"0000-0001-7778-7276","position":4,"is_corresponding":false},{"id":40564,"name":"Sally Temple","orcid":"0000-0001-7301-783X","position":5,"is_corresponding":false},{"id":266771,"name":"Abdallah M. Eteleeb","orcid":"0000-0001-9045-250X","position":6,"is_corresponding":false},{"id":230680,"name":"Carlos Cruchaga","orcid":"0000-0002-0276-2899","position":7,"is_corresponding":false},{"id":27580,"name":"Oscar Harari","orcid":"0000-0002-2635-6975","position":8,"is_corresponding":false},{"id":301876,"name":"Celeste M. Karch","orcid":"0000-0002-6854-5547","position":9,"is_corresponding":false},{"id":995747,"name":"Miguel Minaya","orcid":"0000-0002-2573-6087","position":0,"is_corresponding":true}],"reference_count":116,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:24.307938Z","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":[]}