• Volkan Seyrantepe, Secil Akyildiz Demir, Zehra Kevser Timur, Johanna Von Gerichten, Christian Marsching, Esra Erdemli, Emin Oztas, Kohta Takahashi, Kazunori Yamaguchi, Nurselin Ates, Buket Dönmez Demir, Turgay Dalkara, Katrin Erich, Carsten Hopf, Roger Sandhoff, and Taeko Miyagi.
• Department of Molecular Biology and Genetics, Izmir Institute of Technology, 35430 Izmir, Turkey. Electronic address: volkanseyrantepe@iyte.edu.tr.
• Exp. Neurol. 2018 Jan 1; 299 (Pt A): 26-41.

AbstractTay-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.Copyright © 2017 Elsevier Inc. All rights reserved.

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