Upstream

September, 2021

One of the things that keeps me going is geeking out on the new research going on to battle ALS. Even though I’m only able to understand every third word, I can usually make out enough to learn about the really cool advances that are occurring. Every so often something comes along that I simply have to share it with you. The fact that I am incapable of getting the facts straight is all part of the fun.

One of the issues that has plagued therapy development is that we don’t know what causes this wretched disease. Researchers have identified a number of downstream impacts, such as oxidation and intracellular communication breakdown. As an example, the trial drug I’m taking attacks the foregoing impacts but gives me, at least statistically, only an extra six months of blogs.

The good folks at Johns Hopkins University may have found a root cause in research funded by the ALS Association. So let’s take a step back. There’s a protein in the nucleus of a cell which is called TDP-43, which stands for something something protein. This protein can actually go through the nuclear membrane and do its thing. It is responsible for protein expression in the cell, whatever that means. In ALS this protein is found in the cytoplasm, but it is all deformed and clumped together. Which sucks because this malformed protein causes the motor neuron cell to die. Uncool bummer.

So what causes the TDP-43 to get all messed up? Enter another protein, CHMP7. Yes, the biological powers that be named a protein after a primate. It so happens that this protein can remodel the pathways in the nuclear membrane through which TDP-43 passes on the way to the cytoplasm. The researchers at Johns Hopkins University determined the mechanism behind the way the CHMP7 remodeled pathways screw up the TDP-43 and release it into the cytoplasm where it kills the cell. This invasion of CHMP7 into the nucleus as part of this process is thought to be an upstream event that starts ALS.

One of the most remarkable aspects of the research is that it is performed on human, rather than mouse, neurons. The researchers built human neurons from pluripotent stem cells derived from a pALS. Using RNA technology, they were able to reduce the CHMP7 from the cultured neurons, not only stopping the cellular destruction but reversing the damage. This is huge, to have damage reversed, even if it is in a petri dish.

The techniques used by the researchers have the added benefit of shortening the time it takes to develop new medications. Still, getting this stuff into a clinical therapy is many years away, assuming it’s effective in a human body. What is most important, however, is that we are seeing potential advances against this wretched disease. Just think, a world without ALS.

See you next time.