{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:41:52Z","timestamp":1768506112130,"version":"3.49.0"},"posted":{"date-parts":[[2023,7,16]]},"group-title":"Cell Biology","reference-count":15,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,7,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in the progranulin (PGRN) encoding gene,\n                  <jats:italic>GRN<\/jats:italic>\n                  , cause familial frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis (NCL) and PGRN is also implicated in Parkinson\u2019s disease (PD). These mutations result in decreased PGRN expression. PGRN is highly expressed in peripheral immune cells and microglia and regulates cell growth, survival, repair, and inflammation. When PGRN is lost, the lysosome becomes dysfunctional, but the exact mechanism by which PGRN plays a role in lysosome function and how this contributes to inflammation and degeneration is not entirely understood. To better understand the role of PGRN in regulating lysosome function, this study examined how loss of\n                  <jats:italic>GRN<\/jats:italic>\n                  impacts total LAMP1 protein expression and cathepsin activities. Using mouse embryonic fibroblasts (MEFs), immunocytochemistry and immunoblotting assays were performed to analyze fluorescent signal from LAMP1 (lysosomal marker) and BMV109 (marker for pan-cathepsin activity).\n                  <jats:italic>GRN<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>-\/-<\/jats:italic>\n                  <\/jats:sup>\n                  MEFs exhibit increased expression of pan-cathepsin activity relative to\n                  <jats:italic>GRN<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>+\/+<\/jats:italic>\n                  <\/jats:sup>\n                  MEFs, and significantly impacts expression of LAMP1. The significant increase in pan-cathepsin activity in the\n                  <jats:italic>GRN<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>-\/-<\/jats:italic>\n                  <\/jats:sup>\n                  MEFs confirms that PGRN loss does alter cathepsin expression, which may be a result of compensatory mechanisms happening within the cell. Using NTAP PGRN added to\n                  <jats:italic>GRN<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>-\/-<\/jats:italic>\n                  <\/jats:sup>\n                  MEFs, specific cathepsin activity is rescued. Further investigations should include assessing LAMP1 and BMV109 expression in microglia from\n                  <jats:italic>GRN<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>-\/-<\/jats:italic>\n                  <\/jats:sup>\n                  mice, in the hopes of understanding the role of PGRN in lysosomal function in immune cells of the central nervous system and the diseases in which it is implicated.\n                <\/jats:p>","DOI":"10.1101\/2023.07.15.549151","type":"posted-content","created":{"date-parts":[[2023,7,16]],"date-time":"2023-07-16T17:05:11Z","timestamp":1689527111000},"source":"Crossref","is-referenced-by-count":1,"title":["Loss of Progranulin Results in Increased Pan-Cathepsin Activity and Reduced LAMP1 Lysosomal Protein"],"prefix":"10.64898","author":[{"given":"Abigail","family":"Anderson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1719-4708","authenticated-orcid":false,"given":"Mal\u00fa G.","family":"Tansey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"2","key":"2023071912501498000_2023.07.15.549151v1.1","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1471-4159.2007.04968.x","article-title":"Progranulin: Normal function and role in neurodegeneration","volume":"104","year":"2008","journal-title":"Journal of Neurochemistry"},{"issue":"1","key":"2023071912501498000_2023.07.15.549151v1.2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s13024-018-0281-5","article-title":"Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice","volume":"13","year":"2018","journal-title":"Molecular Neurodegeneration"},{"key":"2023071912501498000_2023.07.15.549151v1.3","doi-asserted-by":"crossref","unstructured":"Houser, M. C. , Uriarte Huarte, O. , Wallings, R. L. , Keating, C. E. , MacPherson, K. P. , Herrick, M. K. , Kannarkat, G. T. , Kelly, S. D. , Chang, J. , Varvel, N. H. , Rexach, J. E. , & Tansey, M. G. (2022). Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system. Frontiers in Immunology, 13. https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1056417","DOI":"10.3389\/fimmu.2022.1056417"},{"key":"2023071912501498000_2023.07.15.549151v1.4","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3389\/fcell.2019.00113","article-title":"The Lysosome Signaling Platform: Adapting With the Times","volume":"7","year":"2019","journal-title":"Frontiers in Cell and Developmental Biology"},{"key":"2023071912501498000_2023.07.15.549151v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2017.36"},{"issue":"1","key":"2023071912501498000_2023.07.15.549151v1.6","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13024-021-00472-1","article-title":"Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration","volume":"16","year":"2021","journal-title":"Molecular Neurodegeneration"},{"key":"2023071912501498000_2023.07.15.549151v1.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1722344115"},{"issue":"13","key":"2023071912501498000_2023.07.15.549151v1.8","first-page":"e1859","article-title":"Mouse Embryonic Fibroblast Cell Culture and Stimulation","volume":"6","year":"2016","journal-title":"Bio-Protocol"},{"key":"2023071912501498000_2023.07.15.549151v1.9","doi-asserted-by":"crossref","unstructured":"Simon, M. J. , Logan, T. , DeVos, S. L. , & Di Paolo, G. (2022). Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia. Trends in Cell Biology. https:\/\/doi.org\/10.1016\/j.tcb.2022.09.006","DOI":"10.1016\/j.tcb.2022.09.006"},{"issue":"10","key":"2023071912501498000_2023.07.15.549151v1.10","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1016\/j.bmc.2017.09.039","article-title":"Peptides for optical medical imaging and steps towards therapy","volume":"26","year":"2018","journal-title":"Bioorganic & Medicinal Chemistry"},{"key":"2023071912501498000_2023.07.15.549151v1.11","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.bbrc.2022.04.064","article-title":"Overexpression of progranulin increases pathological protein accumulation by suppressing autophagic flux","volume":"611","year":"2022","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"2023071912501498000_2023.07.15.549151v1.12","doi-asserted-by":"crossref","unstructured":"Tansey, M. G. , Wallings, R. L. , Houser, M. C. , Herrick, M. K. , Keating, C. E. , & Joers, V. (2022). Inflammation and immune dysfunction in Parkinson disease. Nature Reviews Immunology, 22(11), Article 11. https:\/\/doi.org\/10.1038\/s41577-022-00684-6","DOI":"10.1038\/s41577-022-00684-6"},{"key":"2023071912501498000_2023.07.15.549151v1.13","unstructured":"The Farese & Walther Lab | Sloan Kettering Institute. (n.d.). Retrieved July 5, 2023, from https:\/\/www.mskcc.org\/research\/ski\/labs\/farese-walther"},{"issue":"7","key":"2023071912501498000_2023.07.15.549151v1.14","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.3390\/cells9071679","article-title":"The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management","volume":"9","year":"2020","journal-title":"Cells"},{"key":"2023071912501498000_2023.07.15.549151v1.15","doi-asserted-by":"crossref","first-page":"15277","DOI":"10.1038\/ncomms15277","article-title":"Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations","volume":"8","year":"2017","journal-title":"Nature Communications"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.07.15.549151","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:56:08Z","timestamp":1768452968000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.07.15.549151"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,16]]},"references-count":15,"URL":"https:\/\/doi.org\/10.1101\/2023.07.15.549151","relation":{},"subject":[],"published":{"date-parts":[[2023,7,16]]},"subtype":"preprint"}}