guest ::
| Home > Publications Database > Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations. > print |
| Home > Publications Database > Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations. > print |
| 001 | 140584 | ||
| 005 | 20240321220833.0 | ||
| 024 | 7 | _ | |a 10.1074/jbc.RA118.006311 |2 doi |
| 024 | 7 | _ | |a pmid:30662006 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC6422076 |2 pmc |
| 024 | 7 | _ | |a 0021-9258 |2 ISSN |
| 024 | 7 | _ | |a 1067-8816 |2 ISSN |
| 024 | 7 | _ | |a 1083-351X |2 ISSN |
| 024 | 7 | _ | |a altmetric:55338395 |2 altmetric |
| 037 | _ | _ | |a DZNE-2020-06906 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 540 |
| 100 | 1 | _ | |a Woeste, Marina A |b 0 |
| 245 | _ | _ | |a Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations. |
| 260 | _ | _ | |a Bethesda, Md. |c 2019 |b Soc.60645 |
| 264 | _ | 1 | |3 online |2 Crossref |b American Society for Biochemistry & Molecular Biology (ASBMB) |c 2019-01-20 |
| 264 | _ | 1 | |3 print |2 Crossref |b American Society for Biochemistry & Molecular Biology (ASBMB) |c 2019-03-15 |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1588089624_27525 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a The nonlysosomal glucosylceramidase β2 (GBA2) catalyzes the hydrolysis of glucosylceramide to glucose and ceramide. Mutations in the human GBA2 gene have been associated with hereditary spastic paraplegia (HSP), autosomal-recessive cerebellar ataxia (ARCA), and the Marinesco-Sjögren-like syndrome. However, the underlying molecular mechanisms are ill-defined. Here, using biochemistry, immunohistochemistry, structural modeling, and mouse genetics, we demonstrate that all but one of the spastic gait locus #46 (SPG46)-connected mutations cause a loss of GBA2 activity. We demonstrate that GBA2 proteins form oligomeric complexes and that protein-protein interactions are perturbed by some of these mutations. To study the pathogenesis of GBA2-related HSP and ARCA in vivo, we investigated GBA2-KO mice as a mammalian model system. However, these mice exhibited a high phenotypic variance and did not fully resemble the human phenotype, suggesting that mouse and human GBA2 differ in function. Whereas some GBA2-KO mice displayed a strong locomotor defect, others displayed only mild alterations of the gait pattern and no signs of cerebellar defects. On a cellular level, inhibition of GBA2 activity in isolated cerebellar neurons dramatically affected F-actin dynamics and reduced neurite outgrowth, which has been associated with the development of neurological disorders. Our results shed light on the molecular mechanism underlying the pathogenesis of GBA2-related HSP and ARCA and reveal species-specific differences in GBA2 function in vivo. |
| 536 | _ | _ | |a 341 - Molecular Signaling (POF3-341) |0 G:(DE-HGF)POF3-341 |c POF3-341 |f POF III |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, |
| 650 | _ | 7 | |a beta-Glucosidase |0 EC 3.2.1.21 |2 NLM Chemicals |
| 650 | _ | 7 | |a beta-glucosidase 2, mouse |0 EC 3.2.1.21 |2 NLM Chemicals |
| 650 | _ | 7 | |a GBA2 protein, human |0 EC 3.2.1.45 |2 NLM Chemicals |
| 650 | _ | 2 | |a Glucosylceramidase |2 MeSH |
| 650 | _ | 2 | |a Animals |2 MeSH |
| 650 | _ | 2 | |a Biocatalysis |2 MeSH |
| 650 | _ | 2 | |a Cerebellar Ataxia: genetics |2 MeSH |
| 650 | _ | 2 | |a Cerebellar Ataxia: metabolism |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Locomotion: genetics |2 MeSH |
| 650 | _ | 2 | |a Loss of Function Mutation |2 MeSH |
| 650 | _ | 2 | |a Mice |2 MeSH |
| 650 | _ | 2 | |a Mice, Knockout |2 MeSH |
| 650 | _ | 2 | |a Spastic Paraplegia, Hereditary: genetics |2 MeSH |
| 650 | _ | 2 | |a Spastic Paraplegia, Hereditary: metabolism |2 MeSH |
| 650 | _ | 2 | |a Species Specificity |2 MeSH |
| 650 | _ | 2 | |a beta-Glucosidase: antagonists & inhibitors |2 MeSH |
| 650 | _ | 2 | |a beta-Glucosidase: deficiency |2 MeSH |
| 650 | _ | 2 | |a beta-Glucosidase: genetics |2 MeSH |
| 650 | _ | 2 | |a beta-Glucosidase: metabolism |2 MeSH |
| 700 | 1 | _ | |a Stern, Sina |0 P:(DE-2719)2810277 |b 1 |u dzne |
| 700 | 1 | _ | |a Raju, Diana N |b 2 |
| 700 | 1 | _ | |a Grahn, Elena |b 3 |
| 700 | 1 | _ | |a Dittmann, Dominik |b 4 |
| 700 | 1 | _ | |a Gutbrod, Katharina |b 5 |
| 700 | 1 | _ | |a Dörmann, Peter |b 6 |
| 700 | 1 | _ | |a Hansen, Jan N |0 P:(DE-HGF)0 |b 7 |
| 700 | 1 | _ | |a Schonauer, Sophie |b 8 |
| 700 | 1 | _ | |a Marx, Carina E |b 9 |
| 700 | 1 | _ | |a Hamzeh, Hussein |b 10 |
| 700 | 1 | _ | |a Körschen, Heinz G |b 11 |
| 700 | 1 | _ | |a Aerts, Johannes M F G |b 12 |
| 700 | 1 | _ | |a Bönigk, Wolfgang |b 13 |
| 700 | 1 | _ | |a Endepols, Heike |b 14 |
| 700 | 1 | _ | |a Sandhoff, Roger |b 15 |
| 700 | 1 | _ | |a Geyer, Matthias |b 16 |
| 700 | 1 | _ | |a Berger, Thomas K |b 17 |
| 700 | 1 | _ | |a Bradke, Frank |0 P:(DE-2719)2810270 |b 18 |u dzne |
| 700 | 1 | _ | |a Wachten, Dagmar |0 P:(DE-HGF)0 |b 19 |e Corresponding author |
| 773 | 1 | 8 | |a 10.1074/jbc.ra118.006311 |b : American Society for Biochemistry & Molecular Biology (ASBMB), 2019-01-20 |n 11 |p 3853-3871 |3 journal-article |2 Crossref |t Journal of Biological Chemistry |v 294 |y 2019 |x 0021-9258 |
| 773 | _ | _ | |a 10.1074/jbc.RA118.006311 |g Vol. 294, no. 11, p. 3853 - 3871 |0 PERI:(DE-600)1474604-9 |n 11 |q 294:11<3853 - 3871 |p 3853-3871 |t The journal of biological chemistry |v 294 |y 2019 |x 0021-9258 |
| 856 | 7 | _ | |2 Pubmed Central |u http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422076 |
| 909 | C | O | |o oai:pub.dzne.de:140584 |p VDB |
| 910 | 1 | _ | |a Deutsches Zentrum für Neurodegenerative Erkrankungen |0 I:(DE-588)1065079516 |k DZNE |b 1 |6 P:(DE-2719)2810277 |
| 910 | 1 | _ | |a Deutsches Zentrum für Neurodegenerative Erkrankungen |0 I:(DE-588)1065079516 |k DZNE |b 18 |6 P:(DE-2719)2810270 |
| 913 | 1 | _ | |a DE-HGF |b Forschungsbereich Gesundheit |l Erkrankungen des Nervensystems |1 G:(DE-HGF)POF3-340 |0 G:(DE-HGF)POF3-341 |2 G:(DE-HGF)POF3-300 |v Molecular Signaling |x 0 |
| 914 | 1 | _ | |y 2019 |
| 915 | _ | _ | |a JCR |0 StatID:(DE-HGF)0100 |2 StatID |b J BIOL CHEM : 2019 |d 2021-05-04 |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0200 |2 StatID |b SCOPUS |d 2021-05-04 |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0300 |2 StatID |b Medline |d 2021-05-04 |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0320 |2 StatID |b PubMed Central |d 2021-05-04 |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0600 |2 StatID |b Ebsco Academic Search |d 2021-05-04 |
| 915 | _ | _ | |a Peer Review |0 StatID:(DE-HGF)0030 |2 StatID |b ASC |d 2021-05-04 |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0199 |2 StatID |b Clarivate Analytics Master Journal List |d 2021-05-04 |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)1030 |2 StatID |b Current Contents - Life Sciences |d 2021-05-04 |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)1050 |2 StatID |b BIOSIS Previews |d 2021-05-04 |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0150 |2 StatID |b Web of Science Core Collection |d 2021-05-04 |
| 915 | _ | _ | |a IF < 5 |0 StatID:(DE-HGF)9900 |2 StatID |d 2021-05-04 |
| 920 | 1 | _ | |0 I:(DE-2719)1013002 |k AG Bradke |l Axon Growth and Regeneration |x 0 |
| 980 | _ | _ | |a journal |
| 980 | _ | _ | |a VDB |
| 980 | _ | _ | |a I:(DE-2719)1013002 |
| 980 | _ | _ | |a UNRESTRICTED |
| 999 | C | 5 | |a 10.1074/jbc.M610544200 |9 -- missing cx lookup -- |2 Crossref |o 10.1074/jbc.M610544200 |
| 999 | C | 5 | |a 10.1074/jbc.M112.414714 |9 -- missing cx lookup -- |2 Crossref |o 10.1074/jbc.M112.414714 |
| 999 | C | 5 | |a 10.1172/JCI29224 |9 -- missing cx lookup -- |2 Crossref |o 10.1172/JCI29224 |
| 999 | C | 5 | |a 10.1371/journal.pgen.1005063 |9 -- missing cx lookup -- |2 Crossref |o 10.1371/journal.pgen.1005063 |
| 999 | C | 5 | |a 10.1073/pnas.262586099 |9 -- missing cx lookup -- |2 Crossref |o 10.1073/pnas.262586099 |
| 999 | C | 5 | |a 10.1093/humrep/dei463 |9 -- missing cx lookup -- |2 Crossref |o 10.1093/humrep/dei463 |
| 999 | C | 5 | |a 10.1074/jbc.M702387200 |9 -- missing cx lookup -- |2 Crossref |o 10.1074/jbc.M702387200 |
| 999 | C | 5 | |a 10.1007/s11064-012-0719-z |9 -- missing cx lookup -- |2 Crossref |o 10.1007/s11064-012-0719-z |
| 999 | C | 5 | |a 10.1371/journal.pone.0138107 |9 -- missing cx lookup -- |2 Crossref |o 10.1371/journal.pone.0138107 |
| 999 | C | 5 | |a 10.1007/s00415-013-7206-6 |9 -- missing cx lookup -- |2 Crossref |o 10.1007/s00415-013-7206-6 |
| 999 | C | 5 | |a 10.1016/j.ajhg.2012.12.012 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.ajhg.2012.12.012 |
| 999 | C | 5 | |a 10.1371/journal.pone.0169309 |9 -- missing cx lookup -- |2 Crossref |o 10.1371/journal.pone.0169309 |
| 999 | C | 5 | |a 10.1016/j.ajhg.2012.11.021 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.ajhg.2012.11.021 |
| 999 | C | 5 | |a 10.1111/ahg.12045 |9 -- missing cx lookup -- |2 Crossref |o 10.1111/ahg.12045 |
| 999 | C | 5 | |a 10.1016/S0140-6736(83)92879-9 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/S0140-6736(83)92879-9 |
| 999 | C | 5 | |a 10.1055/s-0031-1299787 |9 -- missing cx lookup -- |2 Crossref |o 10.1055/s-0031-1299787 |
| 999 | C | 5 | |a 10.3389/fnmol.2017.00386 |9 -- missing cx lookup -- |2 Crossref |o 10.3389/fnmol.2017.00386 |
| 999 | C | 5 | |a 10.1016/j.bbrc.2015.07.112 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.bbrc.2015.07.112 |
| 999 | C | 5 | |a 10.1021/acschembio.6b00192 |9 -- missing cx lookup -- |2 Crossref |o 10.1021/acschembio.6b00192 |
| 999 | C | 5 | |a 10.1021/acscentsci.7b00214 |9 -- missing cx lookup -- |2 Crossref |o 10.1021/acscentsci.7b00214 |
| 999 | C | 5 | |a 10.1093/nar/gky427 |9 -- missing cx lookup -- |2 Crossref |o 10.1093/nar/gky427 |
| 999 | C | 5 | |a 10.1107/S2059798316008482 |9 -- missing cx lookup -- |2 Crossref |o 10.1107/S2059798316008482 |
| 999 | C | 5 | |y 1991 |2 Crossref |o Esen 1991 |
| 999 | C | 5 | |a 10.1074/jbc.M116.762831 |9 -- missing cx lookup -- |2 Crossref |o 10.1074/jbc.M116.762831 |
| 999 | C | 5 | |a 10.1074/jbc.M110641200 |9 -- missing cx lookup -- |2 Crossref |o 10.1074/jbc.M110641200 |
| 999 | C | 5 | |a 10.1186/1750-1172-8-151 |9 -- missing cx lookup -- |2 Crossref |o 10.1186/1750-1172-8-151 |
| 999 | C | 5 | |a 10.1074/jbc.273.41.26522 |9 -- missing cx lookup -- |2 Crossref |o 10.1074/jbc.273.41.26522 |
| 999 | C | 5 | |a 10.1089/neu.2006.23.537 |9 -- missing cx lookup -- |2 Crossref |o 10.1089/neu.2006.23.537 |
| 999 | C | 5 | |a 10.1016/j.clineuro.2018.02.042 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.clineuro.2018.02.042 |
| 999 | C | 5 | |a 10.2217/14622416.9.6.717 |9 -- missing cx lookup -- |2 Crossref |o 10.2217/14622416.9.6.717 |
| 999 | C | 5 | |a 10.1186/1477-7827-5-1 |9 -- missing cx lookup -- |2 Crossref |o 10.1186/1477-7827-5-1 |
| 999 | C | 5 | |a 10.1016/j.bcmd.2013.04.005 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.bcmd.2013.04.005 |
| 999 | C | 5 | |a 10.1185/03007990802576518 |9 -- missing cx lookup -- |2 Crossref |o 10.1185/03007990802576518 |
| 999 | C | 5 | |a 10.1002/14651858.CD010324.pub2 |9 -- missing cx lookup -- |2 Crossref |o 10.1002/14651858.CD010324.pub2 |
| 999 | C | 5 | |a 10.1172/JCI200420138 |9 -- missing cx lookup -- |2 Crossref |o 10.1172/JCI200420138 |
| 999 | C | 5 | |a 10.1007/s10048-010-0252-7 |9 -- missing cx lookup -- |2 Crossref |o 10.1007/s10048-010-0252-7 |
| 999 | C | 5 | |a 10.1016/j.ymgme.2017.07.002 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.ymgme.2017.07.002 |
| 999 | C | 5 | |y 1993 |2 Crossref |o Harel 1993 |
| 999 | C | 5 | |a 10.1046/j.1471-4159.1995.65041551.x |9 -- missing cx lookup -- |2 Crossref |o 10.1046/j.1471-4159.1995.65041551.x |
| 999 | C | 5 | |a 10.1523/JNEUROSCI.17-09-02929.1997 |9 -- missing cx lookup -- |2 Crossref |o 10.1523/JNEUROSCI.17-09-02929.1997 |
| 999 | C | 5 | |a 10.1111/jnc.14146 |9 -- missing cx lookup -- |2 Crossref |o 10.1111/jnc.14146 |
| 999 | C | 5 | |a 10.1016/j.cell.2013.12.009 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.cell.2013.12.009 |
| 999 | C | 5 | |a 10.1002/dneu.20734 |9 -- missing cx lookup -- |2 Crossref |o 10.1002/dneu.20734 |
| 999 | C | 5 | |a 10.1016/j.cub.2012.04.019 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.cub.2012.04.019 |
| 999 | C | 5 | |a 10.4161/sgtp.27974 |9 -- missing cx lookup -- |2 Crossref |o 10.4161/sgtp.27974 |
| 999 | C | 5 | |a 10.1016/j.expneurol.2004.09.016 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.expneurol.2004.09.016 |
| 999 | C | 5 | |a 10.1016/bs.mie.2017.06.039 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/bs.mie.2017.06.039 |
| 999 | C | 5 | |a 10.1016/j.bbalip.2011.02.005 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.bbalip.2011.02.005 |
| 999 | C | 5 | |a 10.1194/jlr.M064923 |9 -- missing cx lookup -- |2 Crossref |o 10.1194/jlr.M064923 |
| 999 | C | 5 | |a 10.1016/j.bbamem.2008.01.001 |9 -- missing cx lookup -- |2 Crossref |o 10.1016/j.bbamem.2008.01.001 |
| 999 | C | 5 | |a 10.1002/jnr.21147 |9 -- missing cx lookup -- |2 Crossref |o 10.1002/jnr.21147 |
| 999 | C | 5 | |a 10.1038/nprot.2007.294 |9 -- missing cx lookup -- |2 Crossref |o 10.1038/nprot.2007.294 |
| 999 | C | 5 | |a 10.1007/978-1-4939-0844-8_15 |9 -- missing cx lookup -- |2 Crossref |o 10.1007/978-1-4939-0844-8_15 |
| Library | Collection | CLSMajor | CLSMinor | Language | Author |
|---|