Mouse models of Tay–Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism

Abstract

Tay-Sachs and Sandhoff diseases are clinically similar neurodegenerative disorders. These two sphingolipidoses are characterized by a heritable absence of beta-hexosaminidase A resulting in defective GM2 ganglioside degradation. Through disruption of the Hexa and Hexb genes in embryonic stem cells, we have established mouse models corresponding to each disease. Unlike the two human disorders, the two mouse models show very different neurologic phenotypes. Although exhibiting biochemical and pathologic features of the disease, the Tay-Sachs model showed no neurological abnormalities. In contrast, the Sandhoff model was severely affected. The phenotypic difference between the two mouse models is the result of differences in the ganglioside degradation pathway between mice and humans.

Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease

“…4C) indicative of increased "anxiety-like" behavior in the hexb−/−mice. We have employed a behavioral test battery to assess a mouse model of Sandhoff disease that we backbred onto the C57BL/6J background.We demonstrated deficits in motor activity, and coordination consistent with those previously reported [1,7,8,13,14,16,18,20,22,25,27,28] suggesting no significant effect of genetic background. However, we were also able to detect deficits as early as 66 days using the balance beam test.…”

“…However, we were also able to detect deficits as early as 66 days using the balance beam test. Importantly, we have now extended the range of behavioral assays to include tests of cognitive function which demonstrate memory deficits and increased "anxiety-like" behavior.Although we cannot rule out peripheral factors that could affect motor performance [13,22,25], we suggest this is not primary cause of the poor coordination in the balance beam and rotarod that we demonstrate here. The mice did not have abnormal grip (hexb−/ −8.6 ± 1.4 s and hexb+/+ 13.3 ± 2.5 s) and exhibited voluntary activity and exploration within normal ranges at the time points tested.…”

“…Sandhoff disease arises from defects in the gene encoding the β-subunit (hexb) of β-Nacetyl-d-hexosaminide N-acetylhexosaminohydrolase (EC 3.2.1.52) normally involved in the sequential catabolism of gangliosides and other glycoconjugates [11]. Sandhoff patients have widespread brain pathology which results in clinical symptoms including progressive mental and motor deterioration [10,11,21].Two transgenic murine models of Sandhoff disease exist [23,25] that, like the human equivalent, exhibit premature death and display widespread neuronal storage of ganglioside, in addition to gliotic and inflammatory reactions and neuronal cell death [11,16,23,25,27]. The Sandhoff models have engendered much research directed at overcoming the challenges [1,2,4,11,14,15,18,20].…”

“…Both latency (time to cross the beam from end to end) and number of slips (each time a paw fell under the beam midline) were assessed as measures of motor coordination. In the rotarod test, latency to fall from a rotating rod (acceleration increased by 0.5 cm/s every 5 s) was scored automatically with infrared sensors in a Rotamex 5 rotarod (Columbus Inst, Ohio) with four trials per day over 2 days.Behavioral tests were primarily conducted on mice of 79(±2) days old, an age that in most previous assays showed no deficits, but were also performed on some at 66(± 2) and 97(± 2) days when had been typically reported as normal or displaying deficits, respectively [1,4,7,8,13,14,16,18,20,22,25,27,28]. All data are shown as mean ± S.E.M.…”

Gangliosides as apoptotic signals in ER stress response

“…48,56 However, unlike the human disorders, the two GM2-gangliosidosis mouse models 57 In contrast, Sandhoff mice present with a severe and rapidly progressive neurodegenerative course. 58 In the CNS of Tay-Sachs and GM1 mice, a neuraminidase efficiently desialylates the GM1 and GM2 into their corresponding asialo derivatives, GA1 and GA2, that accumulate in massive amounts as the animals age. 48,57 In the GM1 mouse model, this phenotype is accompanied by gradual deterioration of motor functions 48,56 and progressive CNS inflammation.…”