% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Woeste:140584,
      author       = {Woeste, Marina A and Stern, Sina and Raju, Diana N and
                      Grahn, Elena and Dittmann, Dominik and Gutbrod, Katharina
                      and Dörmann, Peter and Hansen, Jan N and Schonauer, Sophie
                      and Marx, Carina E and Hamzeh, Hussein and Körschen, Heinz
                      G and Aerts, Johannes M F G and Bönigk, Wolfgang and
                      Endepols, Heike and Sandhoff, Roger and Geyer, Matthias and
                      Berger, Thomas K and Bradke, Frank and Wachten, Dagmar},
      title        = {{S}pecies-specific differences in nonlysosomal
                      glucosylceramidase {GBA}2 function underlie locomotor
                      dysfunction arising from loss-of-function mutations.},
      journal      = {The journal of biological chemistry},
      volume       = {294},
      number       = {11},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.60645},
      reportid     = {DZNE-2020-06906},
      pages        = {3853-3871},
      year         = {2019},
      abstract     = {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.},
      keywords     = {Glucosylceramidase / Animals / Biocatalysis / Cerebellar
                      Ataxia: genetics / Cerebellar Ataxia: metabolism / Humans /
                      Locomotion: genetics / Loss of Function Mutation / Mice /
                      Mice, Knockout / Spastic Paraplegia, Hereditary: genetics /
                      Spastic Paraplegia, Hereditary: metabolism / Species
                      Specificity / beta-Glucosidase: antagonists $\&$ inhibitors
                      / beta-Glucosidase: deficiency / beta-Glucosidase: genetics
                      / beta-Glucosidase: metabolism / beta-Glucosidase (NLM
                      Chemicals) / beta-glucosidase 2, mouse (NLM Chemicals) /
                      GBA2 protein, human (NLM Chemicals)},
      cin          = {AG Bradke},
      ddc          = {540},
      cid          = {I:(DE-2719)1013002},
      pnm          = {341 - Molecular Signaling (POF3-341)},
      pid          = {G:(DE-HGF)POF3-341},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30662006},
      pmc          = {pmc:PMC6422076},
      doi          = {10.1074/jbc.RA118.006311},
      url          = {https://pub.dzne.de/record/140584},
}