Resulting Condition: Tay-Sachs Disease

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.