{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:34:43Z","timestamp":1791304483565,"version":"4.3.1"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T00:00:00Z","timestamp":1732060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"publisher","award":["R01 NS104390"],"award-info":[{"award-number":["R01 NS104390"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cognitive impairment is a common but poorly understood non-motor aspect of Parkinson\u2019s disease, negatively affecting the patient\u2019s functional capacity and quality of life. The mechanisms underlying cognitive impairment in Parkinson\u2019s disease remain elusive, limiting treatment and prevention strategies.<\/jats:p>\n               <jats:p>This study investigates the molecular and cellular basis of cognitive impairment associated with heterozygous mutations in GBA1, the strongest risk gene for Parkinson\u2019s disease, which encodes glucocerebrosidase, a lysosome enzyme that degrades the glycosphingolipid glucosylceramide into glucose and ceramide. Using a Gba1L444P\/+ mouse model, we provide evidence that L444P heterozygous Gba1 mutation (L444P\/+) causes hippocampus-dependent spatial and reference memory deficits independently of \u03b1-synuclein (\u03b1Syn) accumulation, glucocerebrosidase lipid substrate accumulation, dopaminergic dysfunction and motor deficits. The mutation disrupts hippocampal synaptic plasticity and basal synaptic transmission by reducing the density of hippocampal CA3\u2013CA1 synapses, a mechanism that is dissociated from \u03b1Syn-mediated presynaptic neurotransmitter release. Using a well-characterized Thy1-\u03b1Syn pre-manifest Parkinson\u2019s disease mouse model overexpressing wild-type human \u03b1Syn, we find that the L444P\/+ mutation exacerbates hippocampal synaptic \u03b1Syn accumulation, synaptic and cognitive impairment in young Gba1L444P\/+:Thy1-\u03b1Syn double mutant animals. With age, Thy1-\u03b1Syn mice manifest motor symptoms, and the double mutant mice exhibit more exacerbated synaptic and motor impairment than the Thy1-\u03b1Syn mice.<\/jats:p>\n               <jats:p>Taken together, our results suggest that heterozygous L444P GBA1 mutation alone perturbs hippocampal synaptic structure and function, imposing a subclinical pathological burden for cognitive impairment. When co-existing \u03b1Syn overexpression is present, heterozygous L444P GBA1 mutation interacts with \u03b1Syn pathology to accelerate Parkinson\u2019s disease-related cognitive impairment and motor symptoms.<\/jats:p>","DOI":"10.1093\/brain\/awae380","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T01:35:23Z","timestamp":1732066523000},"page":"1621-1638","source":"Crossref","is-referenced-by-count":9,"title":["Synaptic and cognitive impairment associated with L444P heterozygous glucocerebrosidase mutation"],"prefix":"10.1093","volume":"148","author":[{"given":"Wudu","family":"Lado","sequence":"first","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahrom","family":"Ham","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey Yuen","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio Pablo","family":"Sardi","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi , Cambridge, MA 02141 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