{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:44:50Z","timestamp":1791812690697,"version":"4.3.4"},"reference-count":78,"publisher":"American Society for Clinical Investigation","issue":"22","license":[{"start":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T00:00:00Z","timestamp":1637539200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["NS083706"],"award-info":[{"award-number":["NS083706"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["NS088321"],"award-info":[{"award-number":["NS088321"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["MH119803"],"award-info":[{"award-number":["MH119803"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Lo Family Fellowship for Excellence in Stem Cell Research","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["NS007224"],"award-info":[{"award-number":["NS007224"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National institutes on aging","award":["AG066447"],"award-info":[{"award-number":["AG066447"]}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["AG074609"],"award-info":[{"award-number":["AG074609"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,22]]},"abstract":"<jats:p>\n                    Genetic variants in\n                    <jats:italic>Granulin<\/jats:italic>\n                    (\n                    <jats:italic>GRN<\/jats:italic>\n                    ), which encodes the secreted glycoprotein progranulin (PGRN), are associated with several neurodegenerative diseases, including frontotemporal lobar degeneration, neuronal ceroid lipofuscinosis, and Alzheimer\u2019s disease. These genetic alterations manifest in pathological changes due to a reduction of PGRN expression; therefore, identifying factors that can modulate PGRN levels in vivo would enhance our understanding of PGRN in neurodegeneration and could reveal novel potential therapeutic targets. Here, we report that modulation of the endocytosis\/lysosomal pathway via reduction of Nemo-like kinase (Nlk) in microglia, but not in neurons, can alter total brain Pgrn levels in mice. We demonstrate that Nlk reduction promotes Pgrn degradation by enhancing its trafficking through the endocytosis\/lysosomal pathway, specifically in microglia. Furthermore, genetic interaction studies in mice showed that\n                    <jats:italic>Nlk<\/jats:italic>\n                    heterozygosity in\n                    <jats:italic>Grn<\/jats:italic>\n                    haploinsufficient mice further reduces Pgrn levels and induces neuropathological phenotypes associated with PGRN deficiency. Our results reveal a mechanism for Pgrn level regulation in the brain through the active catabolism by microglia and provide insights into the pathophysiology of PGRN-associated diseases.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.136147","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T12:02:00Z","timestamp":1633608120000},"source":"Crossref","is-referenced-by-count":14,"title":["Microglia regulate brain progranulin levels through the endocytosis\/lysosomal pathway"],"prefix":"10.1172","volume":"6","author":[{"given":"Tingting","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3160-6270","authenticated-orcid":true,"given":"Leon","family":"Tejwani","sequence":"additional","affiliation":[{"name":"Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut, USA."},{"name":"Department of Neuroscience,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6368-2307","authenticated-orcid":true,"given":"Youngseob","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kokubu","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8642-6640","authenticated-orcid":true,"given":"Kimberly","family":"Luttik","sequence":"additional","affiliation":[{"name":"Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut, USA."},{"name":"Department of Neuroscience,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri M.","family":"Driessen","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janghoo","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA."},{"name":"Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut, USA."},{"name":"Department of Neuroscience,"},{"name":"Program in Cellular Neuroscience, Neurodegeneration and Repair, and"},{"name":"Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,11,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-011-9569-4"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R112.399170"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature05016"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-009-0576-2"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nature05017"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20785"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.04.021"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1001\/2013.jamaneurol.393"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1668-z"},{"issue":"1","key":"B10","first-page":"107","article-title":"C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic","volume":"1","author":"Wojtas","year":"2012","journal-title":"Am J Neurodegener Dis"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090915"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6103-11.2013"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx060"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2014.09.023"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.06.026"},{"issue":"12","key":"B16","first-page":"4639","article-title":"Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia","volume":"24","author":"Yin","year":"2010","journal-title":"FASEB J"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3672"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0097032"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2017.06.012"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-017-1000-9"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2018.11.011"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-4-7"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-7-33"},{"issue":"7","key":"B24","first-page":"2438","article-title":"Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin","volume":"118","author":"Kessenbrock","year":"2008","journal-title":"J Clin Invest"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200712039"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.04.001"},{"issue":"5","key":"B27","first-page":"969","article-title":"Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes","volume":"26","author":"Tanaka","year":"2017","journal-title":"Hum Mol Genet"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3498-17.2019"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-016-0132-1"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2014.12.001"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.07.021"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI63113"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100993"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1860-14.2014"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.09.034"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201502029"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/21674"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/21666"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.46"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80784-9"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02603"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.78"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2009.06400.x"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.01.038"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00922-9"},{"key":"B46","doi-asserted-by":"crossref","unstructured":"Tejwani L, et al. Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration [preprint]. https:\/\/doi.org\/10.1101\/2020.04.19.049395 Posted on bioRxiv April 20, 2020","DOI":"10.1101\/2020.04.19.049395"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-017-0205-9"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3465-12.2013"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24625"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2002.0597"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20256"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-100814-125353"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.12.001"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1126\/science.1231143"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12300"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20140214"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aah5642"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.08.029"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2014.04.003"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091568"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1159\/000093102"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2007.07.020"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.10.016"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.08.004"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1401.025"},{"issue":"suppl 1","key":"B66","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/jnc.13654","article-title":"The clinical spectrum of sporadic and familial forms of frontotemporal dementia","volume":"138","author":"Woollacott","year":"2016","journal-title":"J Neurochem"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2017.36"},{"issue":"4","key":"B68","doi-asserted-by":"crossref","first-page":"ENEURO.0100","DOI":"10.1523\/ENEURO.0100-17.2017","article-title":"Intracellular proteolysis of progranulin generates stable, lysosomal granulins that are haploinsufficient in patients with frontotemporal dementia caused by GRN mutations","volume":"4","author":"Holler","year":"2017","journal-title":"eNeuro"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-017-0196-6"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1719-5"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-018-0281-5"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008295"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1016\/j.pep.2016.09.019"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlx085"},{"key":"B75","doi-asserted-by":"crossref","unstructured":"Zhang T, et al Differential regulation of progranulin derived granulin peptides [preprint]. https:\/\/doi.org\/10.1101\/2021.01.08.425959 Posted on bioRxiv January 14, 2021","DOI":"10.1101\/2021.01.08.425959"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5757-10.2011"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.06.036"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.08493"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/136147\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T23:41:53Z","timestamp":1779147713000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/136147"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,22]]},"references-count":78,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11,22]]},"published-print":{"date-parts":[[2021,11,22]]}},"alternative-id":["10.1172\/jci.insight.136147"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.136147","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,22]]},"article-number":"e136147"}}