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.
The lecture Resulting Condition: Tay-Sachs Disease by Richard Mitchell, MD, PhD is from the course Cellular Housekeeping Functions.
The catabolism of which of the following is defective in Tay-Sachs disease?
Which of the following is associated with Tay-Sachs disease?
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