Resulting Condition: Huntington's Disease

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.