00:01
There are diseases that affect this pathway.
00:05
So, let's say we have taken up a complex structure that has multiple things in it.
00:12
Various lipids, various protein peptides.
00:15
This could be something like low density lipoprotein
or this could be a food particle that has been taken up into the lysosome.
00:25
To be -- to break it down, you have to have various enzymes
and various sequences to degrade each new substrate.
00:33
And eventually, you get down to elemental things,
you get down to just amino acids,
or you get down to just two carbon bits of triglycerides.
00:42
And that's the normal lysosome catabolism pathway.
00:45
If you have defects in any of the enzymes along the way in breaking down
this complex substrate, things are gonna be -- have a bottleneck.
00:54
You're gonna be blocked and not able to go any further,
and those intermediates are going to accumulate.
01:00
And that's essentially all lysosome storage diseases are.
01:06
We've lost or have defective enzymes
in a sequence of degradation of some larger complex substrate.
01:14
So, an example of that, basic concept, real diseases occur because of that, Tay-Sachs disease.
01:22
So, this is an example of a lysosomal storage disease.
01:25
It's an autosomal recessive, it's lethal. It will kill you.
01:29
The clinical manifestation is that there is progressive,
very early motor and cognitive deterioration.
01:36
The central nervous system is impressively affected
because this disease affects the turnover of plasma -- a plasma membrane, glycolipids,
that are very important for the integrity of neurons.
01:49
So, it's really gonna have most of its effect on the central nervous system.
01:54
The eyes also are very rapidly affected, so the patients will have blindness.
01:59
So, those are the kind of major clinical manifestations.
02:02
The defect is a subunit of hexosaminidase A
that is responsible for catabolizing ganglioside GM2,
which is a complex substrate,
into one of the other additional downstream molecules GM3 or ganglioside GM3.
02:22
So, the lysosome was not able to do that.
02:24
And you can see all these other components that can be taken up,
or cells are turning over their normal membranes, would need to be catabolized.
02:34
So, you can imagine that in very short order, after I show you what happens with Tay-Sachs,
we're gonna see little circles with red crosses across them
in all those other enzyme pathways in different diseases labeled that way.
02:47
Okay, so Tay-Sachs is specifically upstream in this ganglioside.
02:52
So, ganglioside is just a glycolipid, and it's fairly complex.
02:56
It requires multiple different enzymes to degrade it,
one of the earliest ones is hexosaminidase A.
03:02
We have that defect. So, we're now no longer able to degrade it.
03:06
And so, the macrophages in the neurons accumulate that ganglioside,
and then we don't recycle membrane appropriately.
03:13
And when that happens in a neuron, the neuron checks out.
03:17
And that's why you get the very rapid progressive motor and cognitive deterioration.
03:22
Okay, as promised, now, imagine all those other arrows going to other substrates.
03:28
Look at all those diseases that happen if there are enzymatic defects.
03:33
These are all lysosomal storage diseases that are real diseases
that affect real people and cause real tragedy.
03:39
And you will memorize these when it comes time for the boards, but right now, it's the concept.
03:45
It's the idea that we have complex substrates that need to be progressively degraded,
and there can be enzyme defects that don't allow that to happen.
03:54
And the lysosomes get big and they can potentially rupture,
but you're not getting the normal turnover of the normal molecules in those cells.