{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T06:54:18Z","timestamp":1779173658066,"version":"3.51.4"},"posted":{"date-parts":[[2023,9,14]]},"group-title":"Neuroscience","reference-count":41,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in the\n                  <jats:italic>GBA1<\/jats:italic>\n                  gene have been identified as a prevalent genetic risk factor for Parkinson\u2019s disease (PD).\n                  <jats:italic>GBA1<\/jats:italic>\n                  mutations impair enzymatic activity, leading to lysosomal dysfunction and elevated levels of \u03b1-synuclein (\u03b1-syn). While most research has primarily focused on GBA1\u2019s role in promoting synucleinopathy, emerging evidence suggests that neuroinflammation may be a key pathogenic alteration caused by GBA1 deficiency. To examine the molecular mechanism underlying GBA1 deficiency-mediated neuroinflammation, we generated\n                  <jats:italic>Gba1<\/jats:italic>\n                  E326K knock-in (KI) mice using the CRISPR\/Cas9 technology, which is linked to an increased risk of PD and dementia with Lewy bodies (DLB). In the ventral midbrain and hippocampus of 24-month-old\n                  <jats:italic>Gba1<\/jats:italic>\n                  E326K KI mice, we found a moderate decline in GBA1 enzymatic activity, a buildup of glucosylceramide, and an increase in microglia density. Furthermore, we observed increased levels of pro-inflammatory cytokines and formation of reactive astrocytes in primary microglia and astrocytes, respectively, cultured from\n                  <jats:italic>Gba1<\/jats:italic>\n                  E326K KI mice following treatment with pathologic \u03b1-syn preformed fibrils (PFF). Additionally, the gut inoculation of \u03b1-syn PFF in\n                  <jats:italic>Gba1<\/jats:italic>\n                  E326K KI mice significantly enhanced the accumulation of Lewy bodies in the dentate gyrus of the hippocampus, accompanied by aggravated neuroinflammation and exacerbated non-motor symptoms. This research significantly enhances our understanding of the\n                  <jats:italic>Gba1<\/jats:italic>\n                  E326K mutation\u2019s involvement in neuroinflammation and the cell-to-cell transmission of pathogenic \u03b1-syn in the brain, thereby opening new therapeutic avenues.\n                <\/jats:p>","DOI":"10.1101\/2023.09.14.557673","type":"posted-content","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T23:25:14Z","timestamp":1694733914000},"source":"Crossref","is-referenced-by-count":3,"title":["Linking\n                  <i>Gba1<\/i>\n                  E326K mutation to microglia activation and mild age-dependent dopaminergic Neurodegeneration"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9363-6010","authenticated-orcid":false,"given":"Sin 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Guk","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyeonwoo","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saebom","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Namshik","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seung-Hwan","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi-Xun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3052-3163","authenticated-orcid":false,"given":"Sangjune","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0864-5239","authenticated-orcid":false,"given":"Han 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