{"doi":"10.1172/jci138207","title":"Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration","abstract":"Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding transactive response DNA-binding protein 43 kDa (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-causing (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 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 life span deficits in 2 distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared through the autophagy/lysosome pathway, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.","journal":"Journal of Clinical Investigation","year":2023,"id":339909,"datarank":0.42498200160843247,"base_score":2.833213344056216,"endowment":2.833213344056216,"self_citation_contribution":0.42498200160843247,"citation_network_contribution":0.0,"self_endowment_contribution":0.42498200160843247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1074276,"name":"Youngseob Jung","orcid":null,"position":1,"is_corresponding":false},{"id":573990,"name":"Hiroshi Kokubu","orcid":"0000-0003-2702-841X","position":2,"is_corresponding":false},{"id":1074277,"name":"Sowmithra Sowmithra","orcid":null,"position":3,"is_corresponding":false},{"id":807702,"name":"Luhan Ni","orcid":"0009-0002-3043-3002","position":4,"is_corresponding":false},{"id":807700,"name":"Chang‐Woo Lee","orcid":"0000-0002-0943-1646","position":5,"is_corresponding":false},{"id":1073908,"name":"Benjamin Sanders","orcid":"0000-0003-3818-598X","position":6,"is_corresponding":false},{"id":1073909,"name":"Jong Seo Lee","orcid":"0000-0002-4009-8220","position":7,"is_corresponding":false},{"id":237106,"name":"Yangfei Xiang","orcid":"0000-0002-6256-6312","position":8,"is_corresponding":false},{"id":375683,"name":"Kimberly P. Luttik","orcid":"0000-0001-8642-6640","position":9,"is_corresponding":false},{"id":573991,"name":"Armand Soriano","orcid":"0009-0009-6619-6281","position":10,"is_corresponding":false},{"id":573992,"name":"Jennifer Yoon","orcid":"0000-0001-9225-9308","position":11,"is_corresponding":false},{"id":573993,"name":"Junhyun Park","orcid":"0000-0003-1366-0238","position":12,"is_corresponding":false},{"id":573994,"name":"Hannah Ro","orcid":"0009-0007-8133-9768","position":13,"is_corresponding":false},{"id":573995,"name":"Hyoungseok Ju","orcid":"0000-0002-6730-2260","position":14,"is_corresponding":false},{"id":256509,"name":"Clara Liao","orcid":"0000-0003-2734-8202","position":15,"is_corresponding":false},{"id":573996,"name":"Sofia Massaro Tieze","orcid":"0000-0001-7545-411X","position":16,"is_corresponding":false},{"id":254055,"name":"Frank Rigo","orcid":"0000-0001-6467-3309","position":17,"is_corresponding":false},{"id":262353,"name":"Paymaan Jafar‐Nejad","orcid":"0000-0001-5176-739X","position":18,"is_corresponding":false},{"id":372058,"name":"Janghoo Lim","orcid":"0000-0002-5331-210X","position":19,"is_corresponding":false},{"id":279389,"name":"Leon Tejwani","orcid":"0000-0002-3160-6270","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:10:49.535464Z","pmid":"37384409","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":[]}