Characterization of Transgenic Mouse Model of Humanized Sialidase

Abstract

<p>Ganglosidoses are a group of fatal neurological disorders which primarily affect children. Pathologically, these disorders need more characterization. The recent development of mouse models of these diseases makes it possible to identify progressive pathological changes within the CNS at the molecular level. Tay Sachs disease is a lysosomal storage disorder characterized by accumulation of GM2 Ganglioside. Targeted Knockout of β-hexosaminidase A (hex a) was generated as a mouse model of Tay Sachs disease; however, the mouse showed little clinical phenotype. The molecular mechanism which allows the hexa-/- mouse to escape the disease involves a metabolic bypass facilitated by lysosomal Sialidase (neu l). In this study we hypothesize that the reason humans have the infantile Tay-Sachs whereas mice do not, is a difference in specificity between human and mouse sialidases. This specificity difference makes the human sialidase unable to hydrolyze GM2 to GA2, which leads to the accumulation of GM2 in neurons and consequently a resulting Tay-Sachs phenotype. In this project, a transgenic mouse expressing human Sialidase under the control of the mouse neul promoter was generated. Then a crossing of this mouse with hexa-/- mouse was done to generate a Tay Sachs mouse expressing human Sialidase. This double transgenic mouse was characterized phenotypically, biochemically and histologically. I found that the double transgenic mice are small in size, have hind limbs spasticity, peculiar posture with Kyphosis, and visual impairments; and around three months of age, which is very early comparing to Tay-Sachs late-onset animal model. Moreover the animals showed muscle weakness and clasping of their hind limbs, and they depicted weird behavior presented in vigorous combing of their faces while standing on their hind limbs and tails. However, these results indicate no significant difference between hexa-/- and the double transgenic (hexa-/-KI+) mice in gangliosides catabolic pathway.</p>