Hello, I'm Don Mahuran,
a senior scientist at The Hospital for Sick Children in Toronto,
Ontario Canada and professor in
the Department of Laboratory Medicine and Pathobiology at the University of Toronto.
My topic is GM2 Gangliosidosis,
which is actually a family of very similar diseases known as Tay-Sachs,
Sandhoff, and the AB-variant form.
These diseases all are caused by the storage of
this rather complex acidic glycolipid known as GM2 ganglioside
in the lysosomes of mainly neuronal cells.
One of the more obvious effects of this storage,
is the development of this retinal cherry-red spot you see on
the right which was noted in Tay-Sachs patients as early as 1880.
Gangliosides are broken down in lysosomes by a series of
sequential cleavage steps removing each of the terminal non-reducing sugars in order.
These reactions are carried out by specific lysosomal exo-glycosidases.
If any one of these exo-glycosidases is deficient,
the degradation stops at that point and can go no further.
As an example, we're looking here at
GM1 ganglioside which is one of the major brain gangliosides.
You can see the chemical structure is being represented by these geometric shapes.
Now GM1 is actually stored in two diseases known as
GM1 ganglisidosis or Morquio type B which differ really
only in phenotype because they are both caused by a deficiency of beta galactosidase
which would normally remove the terminal galactose residue to produce GM2 ganglioside,
which is stored in Tay-Sachs and Sandhoff disease because of
a lack of beta-hexosaminidase A which should normally convert it
into GM 3 ganglioside. GM3 ganglioside is then converted
by neuraminidase and beta-galactosidase again into glucosylceramide.
This compound is stored in
Gaucher's disease because of a lack of beta-glucocerebrosidase,
which would normally remove the glucose residue to give you ceramide.