Toxic Proteins are Like Bananas

You probably know how bananas work - one goes brown and the others soon follow. They also cause other non-banana fruits to ripen quickly because they release a gas called ethene.

In cases of Alzheimer's disease caused by the genetic mutation APP (Amyloid Precursor Protein), we see a similar sort of pattern to this. The whole problem with Alzheimer's and all the plaque build ups are caused by something called Proteotoxicity, basically toxic proteins. And this would make perfect sense if we were talking about a Presenelin precursor protein, but we're not. In theory, APP should only cause toxic characteristics in Beta-Amyloid because it is a predisposition to excessive aggregation with this protein. In reality, however, there is no difference in the amount and type of plaques formed between APP and PSEN - 1. I first realized this while beginning to write the abstract for my project and you can imagine how that started a furiously confused QFT.

When a person possesses these precursors, no matter which protein the mutation is said to target, the misfolding of one substance in the brain leads to the misfolding of others. Just like the bananas. I don't know why that happens and I have not found an answer that I can comprehend, not yet anyway. The point is though, just knowing this fact even if I don't fully understand it, gives me a more clear picture of exactly what I'm dealing with. Last year, I often said that I must "understand the beast that I wish to tackle." Obviously in reference to Alzheimer's. And I think that is no less, but even more true this year. Writing a thesis means that I am saying something - trying to prove a very distinct and original statement about a particular topic/area of study. By extension, that means I also understand the implications of my topic and how it fits into the larger context of things - of humans and what happens to our biology.

After learning about this trend between proteins, I considered how I might observe whether or not it is present in C. Elegans. In short, it's probably possible but I'm not sure I would be able to do it along with the other experiment I have already begun. If there was any theoretical way I could possibly make it work, I would envision such a study being longitudinal (which brings its own multitude of troubles) and being very heavy on the genetic manipulation.

Because its near impossible to differentiate various proteins from one another, without fluorescence, I would have to genetically integrate each strain with multiple kinds of fluorescence for the multiple proteins I wish to study - this would be one of the controlled variables which means they all must be done with the same injection needle, in the same exact location within the gonad, and the proteins would have to include the same exact components (save for phenotypic color expression), be produced by the same person and under the same conditions. That would have to all be possible in order to make the baseline control group happen. After that, I would be charged with growing two experimental strains - the changed variable being the type of precursor protein (SEL -12 or APP). Once I got PCR confirmation that all of these genetics were in order, I would have to synchronize the ages of my sample size and look to see if the types of plaques became more numerous over time or if they were all simply constituted by only Amyloid or only Tau.

So yes, that would be a lot of work and a lot of time and they would have to be continuous intervals of time. Which, unless I could adjust everything perfectly to begin and end during December or April break, means that to figure out this one fact about C. Elegans is kind of impossible for me to do.

Now, although I cannot personally figure out the pathways of these mutations with respect to specific proteins, it has led me closer to ruling out one false drop I may come across in the research I am doing. So I'm studying Glia and trying to decide whether the SEL-12 mutation overwhelms the glia or ablates its function once the irregularity is expressed. One of the ways I can do this is by looking at the rate by which plaques accumulate in the neurons of the worm - if its a linear function, increasing at a steady rate, then that can be an indication showing me that glia lose their function from the beginning. If the plaques accumulate at an exponentially increasing rate, that can mean the opposite - that the glia are overwhelmed and lose function gradually. By keeping in mind this fact of proteotoxicity, I will know to watch out for auto-fluorescence caused by other types of proteins simultaneously building up. If the other non-tau proteins start to aggregate and for some reason contain the GFP marker, then it could appear as an exponential rate of increase. Since I am only looking at tau proteins, including these other proteins' results in my data can compromise the validity of my experiment because I would then be manipulating more than one variable.

That was probably a lot to take in so don't worry, I won't burden you with much more besides this; keep your bananas - and your proteins - isolated.