{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T10:17:59Z","timestamp":1777285079616,"version":"3.51.4"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,4]],"date-time":"2017-05-04T00:00:00Z","timestamp":1493856000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,4]],"date-time":"2017-05-04T00:00:00Z","timestamp":1493856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In 2006, mutations in the granulin gene were identified in patients with familial Frontotemporal Lobar Degeneration. Granulin transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin protein. Granulin mutations were initially found in tau-negative patients, though recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer\u2019s disease and corticobasal degeneration. Moreover, a reduction in progranulin in tau transgenic mice is associated with increasing tau accumulation. To investigate the influence of a decline in progranulin protein on other forms of neurodegenerative-related protein accumulation, human granulin mutation cases were investigated by histochemical and biochemical analyses. Results showed a neuronal and glial tau accumulation in granulin mutation cases. Tau staining revealed neuronal pretangle forms and glial tau in both astrocytes and oligodendrocytes. Furthermore, phosphorylated \u03b1-synuclein-positive structures were also found in oligodendrocytes and the neuropil. Immunoblot analysis of fresh frozen brain tissues revealed that tau was present in the sarkosyl-insoluble fraction, and composed of three- and four-repeat tau isoforms, resembling Alzheimer\u2019s disease. Our data suggest that progranulin reduction might be the cause of multiple proteinopathies due to the accelerating accumulation of abnormal proteins including TDP-43 proteinopathy, tauopathy and \u03b1-synucleinopathy.<\/jats:p>","DOI":"10.1038\/s41598-017-01587-6","type":"journal-article","created":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T14:45:15Z","timestamp":1493390715000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Accumulation of multiple neurodegenerative disease-related proteins in familial frontotemporal lobar degeneration associated with granulin mutation"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2377-9232","authenticated-orcid":false,"given":"Masato","family":"Hosokawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromi","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geidy E.","family":"Serrano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas G.","family":"Beach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew C.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Mann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruhiko","family":"Akiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masato","family":"Hasegawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuaki","family":"Arai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,5,4]]},"reference":[{"key":"1587_CR1","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1084\/jem.20091568","volume":"207","author":"F Yin","year":"2010","unstructured":"Yin, F. et al. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med \n                           207, 117\u2013128, doi:10.1084\/jem.20091568 (2010).","journal-title":"J Exp Med"},{"key":"1587_CR2","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1038\/nm816","volume":"9","author":"Z He","year":"2003","unstructured":"He, Z., Ong, C. H., Halper, J. & Bateman, A. Progranulin is a mediator of the wound response. Nat Med \n                           9, 225\u2013229, doi:10.1038\/nm816 (2003).","journal-title":"Nat Med"},{"key":"1587_CR3","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1016\/S0092-8674(02)01141-8","volume":"111","author":"J Zhu","year":"2002","unstructured":"Zhu, J. et al. Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell \n                           111, 867\u2013878, doi:10.1016\/S0092-8674(02)01141-8 (2002).","journal-title":"Cell"},{"key":"1587_CR4","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1002\/dvdy.10341","volume":"227","author":"R Daniel","year":"2003","unstructured":"Daniel, R., Daniels, E., He, Z. & Bateman, A. Progranulin (acrogranin\/PC cell-derived growth factor\/granulin-epithelin precursor) is expressed in the placenta, epidermis, microvasculature, and brain during murine development. Dev Dyn \n                           227, 593\u2013599, doi:10.1002\/dvdy.10341 (2003).","journal-title":"Dev Dyn"},{"key":"1587_CR5","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1083\/jcb.200712039","volume":"181","author":"P Van Damme","year":"2008","unstructured":"Van Damme, P. et al. Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol \n                           181, 37\u201341, doi:10.1083\/jcb.200712039 (2008).","journal-title":"J Cell Biol"},{"key":"1587_CR6","first-page":"1275","volume":"18","author":"CH Ong","year":"2003","unstructured":"Ong, C. H. & Bateman, A. Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis. Histol Histopathol \n                           18, 1275\u20131288 (2003).","journal-title":"Histol Histopathol"},{"key":"1587_CR7","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.ajpath.2010.11.002","volume":"178","author":"F Pickford","year":"2011","unstructured":"Pickford, F. et al. Progranulin is a chemoattractant for microglia and stimulates their endocytic activity. 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