{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Beta‐glucosidase 2 (GBA2) is a non‐lysosomal glucosylceramidase that catalyzes the hydrolysis of glucosylceramide into glucose and ceramide outside the lysosome. Unlike its lysosomal counterpart GBA1, GBA2 is tightly associated with cellular membranes—primarily at the endoplasmic reticulum and Golgi apparatus—where it plays a pivotal role in maintaining sphingolipid homeostasis by modulating the levels of bioactive lipids (such as ceramide and sphingosine) that are involved in signaling, cell stress responses, and apoptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Mutations or loss of GBA2 activity have been linked to a variety of pathological conditions. For example, genetic ablation or deleterious mutations in the GBA2 gene have been associated with male infertility and globozoospermia due to defects in acrosome formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, GBA2 mutations are now recognized as causative for certain neurodegenerative syndromes—including forms of hereditary spastic paraplegia and cerebellar ataxia—thereby classifying these conditions as glucosylceramide storage diseases with concomitant neurological impairments."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, preclinical studies indicate that alterations in GBA2 activity contribute to aberrant sphingolipid metabolism in other diseases. For instance, in a Gaucher disease model, deletion of GBA2 ameliorated bone defects by normalizing bioactive lipid levels, and crosstalk between GBA1 and GBA2 appears important for modulating glucosylceramide levels in tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Furthermore, structural characterization places GBA2 in the glycoside hydrolase family GH116, offering insight into its substrate specificity and mechanism, while studies using selective inhibitors have refined our understanding of its pharmacological regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings establish that GBA2 is a key mediator of non‐lysosomal glucosylceramide metabolism whose proper function is essential for diverse physiological processes ranging from spermatogenesis and neuronal integrity to bone homeostasis. Dysregulation of GBA2 activity, whether by genetic mutation or enzyme imbalance, thus contributes to a spectrum of clinical pathologies, highlighting its potential as both a biomarker and a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yildiz Yildiz, Heidrun Matern, Bonne Thompson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI29224"}], "href": "https://doi.org/10.1172/JCI29224"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17080196"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17080196"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Rolf G Boot, Marri Verhoek, Wilma Donker-Koopman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of the non-lysosomal glucosylceramidase as beta-glucosidase 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M610544200"}], "href": "https://doi.org/10.1074/jbc.M610544200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17105727"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17105727"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Heinz G Körschen, Yildiz Yildiz, Diana Nancy Raju, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The non-lysosomal β-glucosidase GBA2 is a non-integral membrane-associated protein at the endoplasmic reticulum (ER) and Golgi."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.414714"}], "href": "https://doi.org/10.1074/jbc.M112.414714"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23250757"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23250757"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Klaus Harzer, Yotam Blech-Hermoni, Ehud Goldin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Beta-glucosidase 1 (GBA1) is a second bile acid β-glucosidase in addition to β-glucosidase 2 (GBA2). Study in β-glucosidase deficient mice and humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2012.05.117"}], "href": "https://doi.org/10.1016/j.bbrc.2012.05.117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22659419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22659419"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kristoffer Haugarvoll, Stefan Johansson, Carlos E Rodriguez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GBA2 Mutations Cause a Marinesco-Sjögren-Like Syndrome: Genetic and Biochemical Studies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0169309"}], "href": "https://doi.org/10.1371/journal.pone.0169309"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28052128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28052128"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Elodie Martin, Rebecca Schüle, Katrien Smets, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2012.11.021"}], "href": "https://doi.org/10.1016/j.ajhg.2012.11.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23332916"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23332916"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Monia B Hammer, Ghada Eleuch-Fayache, Lucia V Schottlaender, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2012.12.012"}], "href": "https://doi.org/10.1016/j.ajhg.2012.12.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23332917"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23332917"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Saki Sultana, Jennifer Reichbauer, Rebecca Schüle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2015.07.112"}], "href": "https://doi.org/10.1016/j.bbrc.2015.07.112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26220345"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26220345"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Pramod K Mistry, Jun Liu, Li Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1400768111"}], "href": "https://doi.org/10.1073/pnas.1400768111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24639522"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24639522"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "A Kariminejad, L Schöls, R Schüle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Paediatr Neurol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejpn.2016.05.013"}], "href": "https://doi.org/10.1016/j.ejpn.2016.05.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27292318"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27292318"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Christina M Ridley, Karen E Thur, Jessica Shanahan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "β-Glucosidase 2 (GBA2) activity and imino sugar pharmacology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.463562"}], "href": "https://doi.org/10.1074/jbc.M113.463562"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23880767"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23880767"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Ratana Charoenwattanasatien, Salila Pengthaisong, Imogen Breen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bacterial β-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "ACS Chem Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acschembio.6b00192"}], "href": "https://doi.org/10.1021/acschembio.6b00192"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27115290"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27115290"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "E Clarke, C Jantrachotechatchawan, Y Buhidma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Age-related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurochem Int (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuint.2019.104502"}], "href": "https://doi.org/10.1016/j.neuint.2019.104502"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31299418"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31299418"}]}]}]}