RGD Reference Report - Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease. - Rat Genome Database

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Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease.

Authors: Seyrantepe, Volkan  Demir, Secil Akyildiz  Timur, Zehra Kevser  Von Gerichten, Johanna  Marsching, Christian  Erdemli, Esra  Oztas, Emin  Takahashi, Kohta  Yamaguchi, Kazunori  Ates, Nurselin  Dönmez Demir, Buket  Dalkara, Turgay  Erich, Katrin  Hopf, Carsten  Sandhoff, Roger  Miyagi, Taeko 
Citation: Seyrantepe V, etal., Exp Neurol. 2018 Jan;299(Pt A):26-41. doi: 10.1016/j.expneurol.2017.09.012. Epub 2017 Sep 30.
RGD ID: 13673908
Pubmed: PMID:28974375   (View Abstract at PubMed)
DOI: DOI:10.1016/j.expneurol.2017.09.012   (Journal Full-text)

Tay-Sachs disease is a severe lysosomal storage disorder caused by mutations in Hexa, the gene that encodes for the α subunit of lysosomal ß-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 ß-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Tay-Sachs disease  ISOHexa (Mus musculus)13673908; 13673908 RGD 
Tay-Sachs disease  IGINeu3 (Mus musculus)13673908 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hexa  (hexosaminidase subunit alpha)

Genes (Mus musculus)
Hexa  (hexosaminidase A)

Genes (Homo sapiens)
HEXA  (hexosaminidase subunit alpha)


Additional Information