{"doi":"10.1101/2020.04.19.049395","title":"Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration","abstract":"Abstract Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP , encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a viable approach to therapy development for multiple neurodegenerative disorders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126523,"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":0.957,"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":573990,"name":"Hiroshi Kokubu","orcid":"0000-0003-2702-841X","position":1,"is_corresponding":false},{"id":574384,"name":"Paul J. Lee","orcid":null,"position":2,"is_corresponding":false},{"id":237106,"name":"Yangfei Xiang","orcid":"0000-0002-6256-6312","position":3,"is_corresponding":false},{"id":375683,"name":"Kimberly P. Luttik","orcid":"0000-0001-8642-6640","position":4,"is_corresponding":false},{"id":573991,"name":"Armand Soriano","orcid":"0009-0009-6619-6281","position":5,"is_corresponding":false},{"id":573992,"name":"Jennifer Yoon","orcid":"0000-0001-9225-9308","position":6,"is_corresponding":false},{"id":573993,"name":"Junhyun Park","orcid":"0000-0003-1366-0238","position":7,"is_corresponding":false},{"id":573994,"name":"Hannah Ro","orcid":"0009-0007-8133-9768","position":8,"is_corresponding":false},{"id":573995,"name":"Hyoungseok Ju","orcid":"0000-0002-6730-2260","position":9,"is_corresponding":false},{"id":256509,"name":"Clara Liao","orcid":"0000-0003-2734-8202","position":10,"is_corresponding":false},{"id":573996,"name":"Sofia Massaro Tieze","orcid":"0000-0001-7545-411X","position":11,"is_corresponding":false},{"id":254055,"name":"Frank Rigo","orcid":"0000-0001-6467-3309","position":12,"is_corresponding":false},{"id":262353,"name":"Paymaan Jafar‐Nejad","orcid":"0000-0001-5176-739X","position":13,"is_corresponding":false},{"id":372058,"name":"Janghoo Lim","orcid":"0000-0002-5331-210X","position":14,"is_corresponding":false},{"id":279389,"name":"Leon Tejwani","orcid":"0000-0002-3160-6270","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-18T23:15:23.509897Z","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":[]}