Please use this identifier to cite or link to this item:
https://hdl.handle.net/11147/7501
Title: | Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease | Authors: | Seyrantepe, Volkan Akyıldız Demir, Seçil Timur, Zehra Kevser Von Gerichten, Johanna Marsching, Christian Erdemli, Esra Öztaş, Emin Takahashi, Kohta Yamaguchi, Kazunori Ateş, Nurselin Dönmez Demir, Buket Dalkara, Turgay Erich, Katrin Hopf, Carsten Sandhoff, Roger Miyagi, Taeko |
Keywords: | Ganglioside Sialidase NEU3 Tay-Sachs disease |
Publisher: | Elsevier | 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 4.5 months 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. | URI: | https://doi.org/10.1016/j.expneurol.2017.09.012 https://hdl.handle.net/11147/7501 |
ISSN: | 0014-4886 |
Appears in Collections: | Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection |
Show full item record
CORE Recommender
SCOPUSTM
Citations
43
checked on Nov 15, 2024
WEB OF SCIENCETM
Citations
40
checked on Oct 26, 2024
Page view(s)
416
checked on Nov 18, 2024
Download(s)
860
checked on Nov 18, 2024
Google ScholarTM
Check
Items in GCRIS Repository are protected by copyright, with all rights reserved, unless otherwise indicated.