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@ARTICLE{Seyrantepe:131738,
      author       = {V. Seyrantepe and S. A. Demir and Z. K. Timur and J. Von
                      Gerichten$^*$ and C. Marsching$^*$ and E. Erdemli and E.
                      Oztas and K. Takahashi and K. Yamaguchi and N. Ates and B.
                      Dönmez Demir and T. Dalkara and K. Erich and C. Hopf and R.
                      Sandhoff$^*$ and T. Miyagi},
      title        = {{M}urine {S}ialidase {N}eu3 facilitates {GM}2 degradation
                      and bypass in mouse model of {T}ay-{S}achs disease.},
      journal      = {Experimental neurology},
      volume       = {299},
      number       = {Pt A},
      issn         = {0014-4886},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2018-00044},
      pages        = {26 - 41},
      year         = {2018},
      abstract     = {Tay-Sachs disease is a severe lysosomal storage disorder
                      caused by mutations in Hexa, the gene that encodes for the
                      α subunit of lysosomal β-hexosaminidase A (HEXA), which
                      converts GM2 to GM3 ganglioside. Unexpectedly, Hexa-/- mice
                      have a normal lifespan and show no obvious neurological
                      impairment until at least one year of age. These mice
                      catabolize stored GM2 ganglioside using sialidase(s) to
                      remove sialic acid and form the glycolipid GA2, which is
                      further processed by β-hexosaminidase B. Therefore, the
                      presence of the sialidase (s) allows the consequences of the
                      Hexa defect to be bypassed. To determine if the sialidase
                      NEU3 contributes to GM2 ganglioside degradation, we
                      generated a mouse model with combined deficiencies of HEXA
                      and NEU3. The Hexa-/-Neu3-/- mice were healthy at birth, but
                      died at 1.5 to 4.5months of age. Thin-layer chromatography
                      and mass spectrometric analysis of the brains of
                      Hexa-/-Neu3-/- mice revealed the abnormal accumulation of
                      GM2 ganglioside. Histological and immunohistochemical
                      analysis demonstrated cytoplasmic vacuolation in the
                      neurons. Electron microscopic examination of the brain,
                      kidneys and testes revealed pleomorphic inclusions of many
                      small vesicles and complex lamellar structures. The
                      Hexa-/-Neu3-/- mice exhibited progressive neurodegeneration
                      with neuronal loss, Purkinje cell depletion, and
                      astrogliosis. Slow movement, ataxia, and tremors were the
                      prominent neurological abnormalities observed in these mice.
                      Furthermore, radiographs revealed abnormalities in the
                      skeletal bones of the Hexa-/-Neu3-/- mice. Thus, the
                      Hexa-/-Neu3-/- mice mimic the neuropathological and clinical
                      abnormalities of the classical early-onset Tay-Sachs
                      patients, and provide a suitable model for the future
                      pre-clinical testing of potential treatments for this
                      condition.},
      keywords     = {Glycosphingolipids (NLM Chemicals) / Neu3 protein, mouse
                      (NLM Chemicals) / Neuraminidase (NLM Chemicals) /
                      Hexosaminidase B (NLM Chemicals)},
      cin          = {G131},
      ddc          = {610},
      cid          = {I:(DE-He78)G131-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28974375},
      doi          = {10.1016/j.expneurol.2017.09.012},
      url          = {https://inrepo02.dkfz.de/record/131738},
}