|کد مقاله||کد نشریه||سال انتشار||مقاله انگلیسی||ترجمه فارسی||نسخه تمام متن|
|5629166||1580140||2018||16 صفحه PDF||سفارش دهید||دانلود کنید|
- Tay-Sachs disease (TSD) is an inborn error of metabolism, a prototypical lysosomal storage disease of the nervous system.
- In humans, the fatal infantile acute form is the most common with no current treatment, and palliative care the only options.
- TSD mice did not mimic human infantile TSD although they showed some early pathology and storage of GM2 ganglioside.
- We demostrated that extremely mild disease in TSD mice is likely due to a biochemical bypass, a sialidase.
- Murine sialidase, Neu3, responsible for the degradation of GM2 and new mouse model is suitable for the pre-clinical testing.
Tay-Sachs disease is a severe lysosomal storage disorder caused by mutations in Hexa, the gene that encodes for the Î± subunit of lysosomal Î²-hexosaminidase A (HEXA), which converts GM2 to GM3 ganglioside. Unexpectedly, Hexaâ/â 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 Î²-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 Hexaâ/âÂ Neu3â/â mice were healthy at birth, but died at 1.5 to 4.5Â months of age. Thin-layer chromatography and mass spectrometric analysis of the brains of Hexaâ/âÂ Neu3â/â 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 Hexaâ/âÂ Neu3â/â 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 Hexaâ/âÂ Neu3â/â mice. Thus, the Hexaâ/âÂ Neu3â/â 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.
Journal: Experimental Neurology - Volume 299, Part A, January 2018, Pages 26-41