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Heterozygous carriers of most <jats:italic>GBA1<\/jats:italic> mutations have dramatically increased Parkinson's disease (PD) risk, but the mechanisms and cells affected remain unknown. Glucocerebrosidase expression is relatively enriched in astrocytes, yet the impact of its mutation in these cells has not yet been addressed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Emerging data supporting non\u2010cell\u2010autonomous mechanisms driving PD pathogenesis inspired the first characterization of <jats:italic>GBA1<\/jats:italic>\u2010mutant astrocytes. In addition, we asked whether LRRK2, likewise linked to PD and enriched in astrocytes, intersected with <jats:italic>GBA1<\/jats:italic> phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using heterozygous and homozygous <jats:italic>GBA1 D409V<\/jats:italic> knockin mouse astrocytes, we conducted rigorous biochemical and image\u2010based analyses of lysosomal function and morphology. We also examined basal and evoked cytokine response at the transcriptional and secretory levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The <jats:italic>D409V<\/jats:italic> knockin astrocytes manifested broad deficits in lysosomal morphology and function, as expected. This, however, is the first study to show dramatic defects in basal and TLR4\u2010dependent cytokine production. Albeit to different extents, both the lysosomal dysfunction and inflammatory responses were normalized by inhibition of LRRK2 kinase activity, suggesting functional intracellular crosstalk between glucocerebrosidase and LRRK2 activities in astrocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These data demonstrate novel pathologic effects of a <jats:italic>GBA1<\/jats:italic> mutation on inflammatory responses in astrocytes, indicating the likelihood of broader immunologic changes in GBA\u2010PD patients. Our findings support the involvement of non\u2010cell\u2010autonomous mechanisms contributing to the pathogenesis of <jats:italic>GBA1<\/jats:italic>\u2010linked PD and identify new opportunities to correct these changes with pharmacological intervention. \u00a9 2020 International Parkinson and Movement Disorder Society<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.27994","type":"journal-article","created":{"date-parts":[[2020,2,8]],"date-time":"2020-02-08T04:12:30Z","timestamp":1581135150000},"page":"760-773","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":111,"title":["Lysosome and Inflammatory Defects in <i>GBA1<\/i>\u2010Mutant Astrocytes Are Normalized by LRRK2 Inhibition"],"prefix":"10.1002","volume":"35","author":[{"given":"Anwesha","family":"Sanyal","sequence":"first","affiliation":[{"name":"Ann Romney Center for Neurological Diseases Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts 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