All right, I want to through very, very quickly and briefly, what does the mutant Huntingtin do to a cell? And it turns out that it does everything. That's bad. For example, if we think about a cell, the most fundamental ones are transcription, right? So the transcription, people found that there are transcription factors that are sequestered by mutant Huntingtin, and those factors include but are not limited to, what I listed here. There's TBP, CBP, P53, SP1, these things. They're all sequestered into the aggregates. So that's one way of making a cell sick. How about the DNA structure itself? We know that DNA in our nucleus, it's not spreading out like a noodle. Instead it's winding around the histone, right? A histone itself can be modified. So you have histone acetylation and deacetylation that regulates the gene activity. So mutant Huntingtin obviously, it affects histone acetylation, deacetylation. And there is a proposal that we can use, a drug that inhibits histone deacetylase to alleviate Huntington's disease, maybe not cure, but at least some help, so it's one thing that it does. About a lot of analysis, one thing came out very, very strong. That is people observed in Huntington's disease, those neurons, they have big aggregations. The aggregation contains Huntingtin itself. It contains ubiquitin, and it's a huge structure blocking the cell. I want to show you a picture of that. So you may have nucleus. Nucleus aggregation, you may have cytosolic aggregation. On the right hand side those are just bigger Pictures. Now this protein aggregation observation is not unique in Huntington's disease. It started with people observing Huntington's disease, but then, doctors and scientists looked at other diseases and found it's a universal observation in almost all neuro-degenerative diseases. I listed here some of them for you. For example, you have Huntington's disease HD, in Alzheimer's disease, you have a beta plaque, right? That's extra cellular aggregation. You have intracellular tau, fossil tau. In Parkinson's disease here you have alpha sin nucleo aggregation. It's called Louis body, because Dr. Louis discovered it. In another disease, ALS, it has aggregation. And in CJD FTDP, all of the diseases, they have aggregation one way or the other. Therefore, the question raised at that time was, well, since it always comes with a disease, shall we design drugs and use this one as the bio-marker to test. By dissolving these aggregations, can we help patients? It seems like a very straightforward proposal with a quite good logic, right? We see that all the time, let's dissolve the thing, can we help? What logic problem we have here? Cause and effect. That relationship, by observing aggregation, what does it do to a real cell, a real patient? Is that causative, or it's a product of something. Or it's a byproduct, not so important. We don't know that yet. However, people jumped ahead and really screened for compounds and all that. Several came out like Congo red and all that. Lot's of lots of labs and many pharmaceutical companies were doing that. But interestingly, without knowing whether it's just pathologic or pathogenic. And here's something coming out very, very odd. In one of our observations, we actually put a mutation in the region right after the polyQ. There is a polyproline region, we changed a little bit of that and we have a new mouse model, compared to the one with expectancy ag, normal Huntingtin. This mouse, now the middle one, has the same pathology, exactly like human patients. A full range of those Huntington's disease phenotypes, but it does not have aggregate at all. So this is one very, very shocking experimental data. Seeing Huntington's disease, at least in the model, it does not have to involve aggregation at all. As long as you have the bad molecule, it will kill the neurons anyway. Therefore, it raises a serious doubt by dissolving the Huntingtin aggregation can you rescue the patients? Is it true at all? And of course there are other scientists in cell culture system demonstrated that actually the aggregation is protective That's Steve Finkbeiner at UC San Fransisco. He showed in cell culture system the ones that grew aggregates die later. The ones without aggregation they die early. Therefore, from those two experiments it seems the monomer or oligomer of mutant Huntingtin is real toxic. If you put these bad guys together,
