00:00 Okay, there's a disease. Of course, there's a disease. 00:03 That's what this is all about. 00:05 Basic cell biology, when it goes wrong, leads to disease at a very basic level. 00:11 So, this disease is Huntington's disease. 00:13 And this is due, we think, to defective autophagy. 00:17 So, what happens is that we get accumulation of the huntingtin protein. 00:22 And I'll show you that on the next slide and why we get it, accumulation, why it's misfolded. 00:27 But that protein, because it's accumulating and in a misfolded state, it isn't being degraded, unfortunately, and it limits the formation and the accumulation of the organelles within the autophagosome. 00:40 So, we end up with empty autophagosomes. 00:43 And we never get rid of senescent organelles or large denatured proteins. 00:49 So, we still get the lysosomal fusion, but nothing is happening because of that huntingtin accumulation. 00:57 Let's see what that looks like on the next slide. 00:59 So, we end up basically not degrading old stuff. And that's a problem. 01:03 So, in Huntington's disease, this -- it's -- a number of diseases are like this. 01:10 There are triplet repeats that normally code for an amino acid. 01:15 So, in the normal Huntington's gene, there are CAG repeats that code for glutamine. 01:22 Well, that's fine. And you normally have, in a healthy gene, between 10 and 26 repeats of that CAG. For reasons not yet completely worked out. 01:33 In Huntington's disease, we get expansion of that CAG repeat. 01:38 So, you get the triplet repeat that gets longer and longer and longer with each generation, and we get longer and longer sequences of glutamine. 01:46 And all that glutamine leads to a misfolded huntingtin protein. 01:52 So, now, we have this accumulation of this misfolded protein. 01:57 And you see that aggregate there. 01:59 And that's going to block the formation of the autophagosome. 02:03 So, we can't get rid of the old senescent organelles. 02:06 And as a result, the neurons don't have appropriate cell turnover. 02:11 They end up with defective mitochondria that are senescent and not making ATP appropriately, and you get atrophy, the neurons die. 02:17 So, on the left-hand side is a representation of a normal brain. 02:21 On the right-hand side, we've had massive atrophy over the course of three, four, five decades. 02:28 And we've lost neurons just because we didn't have appropriate autophagy. 02:33 And with that, we've talked about degrading little things and the importance of that, talked about the degrading of big things and the importance of that.
The lecture Resulting Condition: Huntington's Disease by Richard Mitchell, MD, PhD is from the course Cellular Housekeeping Functions.
Which of the following is involved in the pathogenesis of Huntington's disease?
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Greatings from Rio Grande do Sul, Brasil. Great lecture, profesor. I like very much of your classes, this particularly, it is helping me a lot within a presentation that i have to make at my medical school.
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