Hello, my name is Brian Mark.
I'm an Associate Professor of Microbiology at the University of Manitoba, Canada.
I also hold a cross appointment with
the Department of Biochemistry and Medical Genetics at the University of Manitoba.
In this talk, I am to update you on recent advances in
therapeutic strategies that are being explored to treat GM2 gangliosidosis.
This presentation builds upon an excellent in-depth Henry Stuart talk on
GM2 gangliosidosis that was previously provided by Dr. Don Mahuran,
who is a recently retired University of Toronto Professor and former Senior Scientist
at the Toronto Hospital for Sick Children.
GM2 gangliosidosis is a family of
heritable neurodegenerative diseases known as Tay-Sachs,
Sandhoff and the AB-variant form,
all of which results from GM2 ganglioside accumulation in neuronal cells.
The molecule GM2 ganglioside,
is shown here in the schematic.
GM2 ganglioside belongs to a larger family of gangliosides,
which are differentiated from other glycosphingolipids,
due to the presence of
one or more negatively charged sialic acid residues
that are present on their glycan headgroup.
Gangliosides are a major molecular feature on the surface of vertebrate nerve cells,
and are involved in nervous system development and function,
both motor and cognitive.
Gangliosides are degraded in lysosomes by a series of
sequential cleavage steps that are carried out by exoglycosidases.
Here, we are looking at the degradation of GM1 ganglioside,
which is one of four major gangliosides in the vertebrate nervous system.
If any one of the glycosidases is deficient,
the degradation stops at that point and the respective ganglioside begins to accumulate.
These enzymatic deficiencies lead to a series of
lysosomal storage disorders that are associated with GM1 degradation.
Here, we begin with the degradation of GM1 ganglioside,
where the enzyme beta-Galactosidase removes galactose from the non-reducing end,
the glycan headgroup, to generate GM2 ganglioside.
Lack of beta-Galactosidase activity results in GM1 gangliosidosis or Morquio B,
which differs in phenotype only,
because they are both arise from the loss of the same enzyme.
The enzyme beta-Hexosaminidase, removes galactose,
the main residue, from GM2 ganglioside to generate GM3 ganglioside.
Loss of this activity results in Tay-Sachs or Sandhoff disease,
and is the main focus of the talk today.
The AB-variant form of GM2 gangliosidosis results from the loss of another protein,
which I'll describe in a few minutes.
Next, the enzyme neuraminidase removes
the sialic acid sugar from GM3 ganglioside, to generate lactosylceramide.
Loss of neuraminidase results in the lysosomal storage disorder known as sialadosis.
Beta-Galactosidase then removes a second galactose sugar to generate glucosylceramide.
And the final step in the degradation of GM1 ganglioside is the removal of
glucose from the ceramide stem by beta-Glucocerebrosidase.
The loss of this activity results in Gaucher's disease,
which we'll turn to a little bit later.
So throughout this talk,
I've included citations for further reading.
However, they only represent
a small fraction of the extensive research that has been carried out
on GM2 gangliosidosis and lysosomal storage disorders in general.