Okay, there's a disease. Of course, there's a disease.
That's what this is all about.
Basic cell biology, when it goes wrong, leads to disease at a very basic level.
So, this disease is Huntington's disease.
And this is due, we think, to defective autophagy.
So, what happens is that we get accumulation of the huntingtin protein.
And I'll show you that on the next slide and why we get it, accumulation, why it's misfolded.
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.
So, we end up with empty autophagosomes.
And we never get rid of senescent organelles or large denatured proteins.
So, we still get the lysosomal fusion,
but nothing is happening because of that huntingtin accumulation.
Let's see what that looks like on the next slide.
So, we end up basically not degrading old stuff. And that's a problem.
So, in Huntington's disease, this -- it's -- a number of diseases are like this.
There are triplet repeats that normally code for an amino acid.
So, in the normal Huntington's gene, there are CAG repeats that code for glutamine.
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.
In Huntington's disease, we get expansion of that CAG repeat.
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.
And all that glutamine leads to a misfolded huntingtin protein.
So, now, we have this accumulation of this misfolded protein.
And you see that aggregate there.
And that's going to block the formation of the autophagosome.
So, we can't get rid of the old senescent organelles.
And as a result, the neurons don't have appropriate cell turnover.
They end up with defective mitochondria that are senescent
and not making ATP appropriately, and you get atrophy, the neurons die.
So, on the left-hand side is a representation of a normal brain.
On the right-hand side, we've had massive atrophy over the course of three, four, five decades.
And we've lost neurons just because we didn't have appropriate autophagy.
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.