{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:22:12Z","timestamp":1792801332197,"version":"4.5.0"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"9","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,2,26]]},"abstract":"<jats:p>\n                    Mutations of\n                    <jats:italic>GBA1<\/jats:italic>\n                    , the gene encoding glucocerebrosidase, represent a common genetic risk factor for developing the synucleinopathies Parkinson disease (PD) and dementia with Lewy bodies. PD patients with or without\n                    <jats:italic>GBA1<\/jats:italic>\n                    mutations also exhibit lower enzymatic levels of glucocerebrosidase in the central nervous system (CNS), suggesting a possible link between the enzyme and the development of the disease. Previously, we have shown that early treatment with glucocerebrosidase can modulate \u03b1-synuclein aggregation in a presymptomatic mouse model of Gaucher-related synucleinopathy (\n                    <jats:italic>Gba1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>D409V\/D409V<\/jats:italic>\n                    <\/jats:sup>\n                    ) and ameliorate the associated cognitive deficit. To probe this link further, we have now evaluated the efficacy of augmenting glucocerebrosidase activity in the CNS of symptomatic\n                    <jats:italic>Gba1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>D409V\/D409V<\/jats:italic>\n                    <\/jats:sup>\n                    mice and in a transgenic mouse model overexpressing A53T \u03b1-synuclein. Adeno-associated virus-mediated expression of glucocerebrosidase in the CNS of symptomatic\n                    <jats:italic>Gba1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>D409V\/D409V<\/jats:italic>\n                    <\/jats:sup>\n                    mice completely corrected the aberrant accumulation of the toxic lipid glucosylsphingosine and reduced the levels of ubiquitin, tau, and proteinase K-resistant \u03b1-synuclein aggregates. Importantly, hippocampal expression of glucocerebrosidase in\n                    <jats:italic>Gba1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>D409V\/D409V<\/jats:italic>\n                    <\/jats:sup>\n                    mice (starting at 4 or 12 mo of age) also reversed their cognitive impairment when examined using a novel object recognition test. Correspondingly, overexpression of glucocerebrosidase in the CNS of A53T \u03b1-synuclein mice reduced the levels of soluble \u03b1-synuclein, suggesting that increasing the glycosidase activity can modulate \u03b1-synuclein processing and may modulate the progression of \u03b1-synucleinopathies. Hence, increasing glucocerebrosidase activity in the CNS represents a potential therapeutic strategy for\n                    <jats:italic>GBA1<\/jats:italic>\n                    -related and non-\n                    <jats:italic>GBA1<\/jats:italic>\n                    \u2013associated synucleinopathies, including PD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1220464110","type":"journal-article","created":{"date-parts":[[2013,1,8]],"date-time":"2013-01-08T11:50:39Z","timestamp":1357645839000},"page":"3537-3542","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":234,"title":["Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies"],"prefix":"10.1073","volume":"110","author":[{"given":"S. Pablo","family":"Sardi","sequence":"first","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Clarke","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Viel","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monyrath","family":"Chan","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Tamsett","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Treleaven","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Bu","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Sweet","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco A.","family":"Passini","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James C.","family":"Dodge","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Haung","family":"Yu","sequence":"additional","affiliation":[{"name":"Taub Institute for Research on Alzheimer's Disease, Columbia University Medical Center, NY 10032; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L.","family":"Sidman","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seng H.","family":"Cheng","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamya S.","family":"Shihabuddin","sequence":"additional","affiliation":[{"name":"Genzyme, a Sanofi Company, Framingham, MA 01701;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,1,7]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa033277"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0901281"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000276989.17578.02"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70190-4"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182735e9a"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1096-7192(03)00071-4"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2004.04.011"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2010.12.014"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22400"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1108197108"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuro.2009.06.009"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.06.001"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21399"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.03.002"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23614"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318225ab77"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.24945"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2009.54"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp044"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318253d54b"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21192"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.47.5.1113"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-002-0563-3"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1082324"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2004.01.007"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/62.4.389"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(95)11484-E"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2009.01.003"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.237859"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00682-7"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41615"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1159\/000335038"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1087753"},{"key":"e_1_3_3_34_2","doi-asserted-by":"crossref","unstructured":"MG Schlossmacher Alpha-synuclein and synucleinopathies. 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