{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:02:46Z","timestamp":1790708566956,"version":"4.1.0"},"reference-count":67,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Aims:<\/jats:italic>\n                    <\/jats:bold>\n                    Loss-of-function mutations in\n                    <jats:italic toggle=\"yes\">GBA1<\/jats:italic>\n                    , which cause the autosomal recessive lysosomal storage disease, Gaucher disease (GD), are also a key genetic risk factor for the \u03b1-synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies. G\n                    <jats:italic toggle=\"yes\">BA1<\/jats:italic>\n                    encodes for the lysosomal hydrolase glucocerebrosidase and reductions in this enzyme result in the accumulation of the glycolipid substrates glucosylceramide and glucosylsphingosine. Deficits in autophagy and lysosomal degradation pathways likely contribute to the pathological accumulation of \u03b1-synuclein in PD. In this report we used conduritol-\n                    <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                    -epoxide (CBE), a potent selective irreversible competitive inhibitor of glucocerebrosidase, to model reduced glucocerebrosidase activity\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    , and tested whether sustained glucocerebrosidase inhibition in mice could induce neuropathological abnormalities including\n                    <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                    -synucleinopathy, and neurodegeneration.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Results:<\/jats:italic>\n                    <\/jats:bold>\n                    Our data demonstrate that daily systemic CBE treatment over 28 days caused accumulation of insoluble\n                    <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                    -synuclein aggregates in the substantia nigra, and altered levels of proteins involved in the autophagy lysosomal system. These neuropathological changes were paralleled by widespread neuroinflammation, upregulation of complement C1q, abnormalities in synaptic, axonal transport and cytoskeletal proteins, and neurodegeneration.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Innovation:<\/jats:italic>\n                    <\/jats:bold>\n                    A reduction in brain GCase activity has been linked to sporadic PD and normal aging, and may contribute to the susceptibility of vulnerable neurons to degeneration. This report demonstrates that systemic reduction of GCase activity using chemical inhibition, leads to neuropathological changes in the brain reminiscent of\n                    <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                    -synucleinopathy.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Conclusions:<\/jats:italic>\n                    <\/jats:bold>\n                    These data reveal a link between reduced glucocerebrosidase and the development of\n                    <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                    -synucleinopathy and pathophysiological abnormalities in mice, and support the development of GCase therapeutics to reduce\n                    <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                    -synucleinopathy in PD and related disorders.\n                    <jats:italic toggle=\"yes\">Antioxid. Redox Signal<\/jats:italic>\n                    . 23, 550\u2013564.\n                  <\/jats:p>","DOI":"10.1089\/ars.2015.6307","type":"journal-article","created":{"date-parts":[[2015,6,21]],"date-time":"2015-06-21T07:43:29Z","timestamp":1434872609000},"page":"550-564","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":150,"title":["Sustained Systemic Glucocerebrosidase Inhibition Induces Brain \u03b1-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice"],"prefix":"10.1177","volume":"23","author":[{"given":"Emily M.","family":"Rocha","sequence":"first","affiliation":[{"name":"Harvard Medical School\/McLean Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaynor A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Harvard Medical School\/McLean 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