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Most pathogenic\n                    <jats:italic>GRN<\/jats:italic>\n                    mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in\n                    <jats:italic>GRN<\/jats:italic>\n                    mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with\n                    <jats:italic>GRN<\/jats:italic>\n                    mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with\n                    <jats:italic>GRN<\/jats:italic>\n                    mutations (FTD-\n                    <jats:italic>GRN<\/jats:italic>\n                    ) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-\n                    <jats:italic>GRN<\/jats:italic>\n                    patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only \u03b2-glucocerebrosidase exhibited impairment in FTD-\n                    <jats:italic>GRN<\/jats:italic>\n                    patients. Brains from FTD-\n                    <jats:italic>GRN<\/jats:italic>\n                    patients had lower activity than controls, which was associated with lower levels of mature \u03b2-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated \u03b2-glucocerebrosidase. Immunostaining revealed loss of neuronal \u03b2-glucocerebrosidase in FTD-\n                    <jats:italic>GRN<\/jats:italic>\n                    patients. To investigate the effects of progranulin insufficiency on \u03b2-glucocerebrosidase outside of the context of neurodegeneration, we investigated \u03b2-glucocerebrosidase activity in progranulin-insufficient mice. Brains from\n                    <jats:italic>Grn<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice had lower \u03b2-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs \u03b2-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired \u03b2-glucocerebrosidase processing.\n                  <\/jats:p>","DOI":"10.1186\/s40478-019-0872-6","type":"journal-article","created":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T12:02:48Z","timestamp":1577102568000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Impaired \u03b2-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations"],"prefix":"10.1186","volume":"7","author":[{"given":"Andrew E.","family":"Arrant","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R.","family":"Roth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas R.","family":"Boyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya N.","family":"Kashyap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madelyn Q.","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles F.","family":"Murchison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana Marisa","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alissa L.","family":"Nana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Spina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea T.","family":"Grinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce L.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William W.","family":"Seeley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1810-9763","authenticated-orcid":false,"given":"Erik D.","family":"Roberson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,23]]},"reference":[{"key":"872_CR1","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.neuron.2017.01.018","volume":"93","author":"E Aflaki","year":"2017","unstructured":"Aflaki E, Westbroek W, Sidransky E (2017) The complicated relationship between Gaucher disease and parkinsonism: insights from a rare disease. 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