{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:36:04Z","timestamp":1790667364192,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2011,4,6]],"date-time":"2011-04-06T00:00:00Z","timestamp":1302048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2011,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective:<\/jats:title><jats:p>Heterozygous mutations in the <jats:italic>GBA1<\/jats:italic> gene elevate the risk of Parkinson disease and dementia with Lewy bodies; both disorders are characterized by misprocessing of \u03b1\u2010synuclein (SNCA). A loss in lysosomal acid\u2013\u03b2\u2010glucosidase enzyme (GCase) activity due to biallelic <jats:italic>GBA1<\/jats:italic> mutations underlies Gaucher disease. We explored mechanisms for the gene's association with increased synucleinopathy risk.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>We analyzed the effects of wild\u2010type (WT) and several GBA mutants on SNCA in cellular and in vivo models using biochemical and immunohistochemical protocols.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>We observed that overexpression of all GBA mutants examined (N370S, L444P, D409H, D409V, E235A, and E340A) significantly raised human SNCA levels to 121 to 248% of vector control (<jats:italic>p<\/jats:italic> &lt; 0.029) in neural MES23.5 and PC12 cells, but without altering GCase activity. Overexpression of WT GBA in neural and HEK293\u2010SNCA cells increased GCase activity, as expected (ie, to 167% in MES\u2010SNCA, 128% in PC12\u2010SNCA, and 233% in HEK293\u2010SNCA; <jats:italic>p<\/jats:italic> &lt; 0.002), but had mixed effects on SNCA. Nevertheless, in HEK293\u2010SNCA cells high GCase activity was associated with SNCA reduction by \u226432% (<jats:italic>p<\/jats:italic> = 0.009). Inhibition of cellular GCase activity (to 8\u201320% of WT; <jats:italic>p<\/jats:italic> &lt; 0.0017) did not detectably alter SNCA levels. Mutant GBA\u2010induced SNCA accumulation could be pharmacologically reversed in D409V\u2010expressing PC12\u2010SNCA cells by rapamycin, an autophagy\u2010inducer (\u226440%; 10\u03bcM; <jats:italic>p<\/jats:italic> &lt; 0.02). Isofagomine, a GBA chaperone, showed a related trend. In mice expressing two D409V<jats:italic>gba<\/jats:italic> knockin alleles without signs of Gaucher disease (residual GCase activity, \u226520%), we recorded an age\u2010dependent rise of endogenous Snca in hippocampal membranes (125% vs WT at 52 weeks; <jats:italic>p<\/jats:italic> = 0.019). In young Gaucher disease mice (V394L<jats:italic>gba<\/jats:italic>+\/+\/\/prosaposin[<jats:italic>ps<\/jats:italic>]\u2010null\/\/<jats:italic>ps<\/jats:italic>\u2010transgene), which demonstrate neurological dysfunction after age 10 weeks (GCase activity, \u226410%), we recorded no significant change in endogenous Snca levels at 12 weeks of age. However, enhanced neuronal ubiquitin signals and axonal spheroid formation were already present. The latter changes were similar to those seen in three week\u2010old cathepsin D\u2010deficient mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation:<\/jats:title><jats:p>Our results demonstrate that GBA mutants promote SNCA accumulation in a dose\u2010 and time\u2010dependent manner, thereby identifying a biochemical link between <jats:italic>GBA1<\/jats:italic> mutation carrier status and increased synucleinopathy risk. In cell culture models, this gain of toxic function effect can be mitigated by rapamycin. Loss in GCase activity did not immediately raise SNCA concentrations, but first led to neuronal ubiquitinopathy and axonal spheroids, a phenotype shared with other lysosomal storage disorders. ANN NEUROL 2011;<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.22400","type":"journal-article","created":{"date-parts":[[2011,2,18]],"date-time":"2011-02-18T14:40:03Z","timestamp":1298040003000},"page":"940-953","source":"Crossref","is-referenced-by-count":286,"title":["Acid \u03b2\u2010glucosidase mutants linked to gaucher disease, parkinson disease, and lewy body dementia alter \u03b1\u2010synuclein processing"],"prefix":"10.1002","volume":"69","author":[{"given":"Valerie","family":"Cullen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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