Fruit fly and new Alzheimer's Disease mechanism

 Researchers at the Tokyo Metropolitan University have presumably discovered a new mechanism by which tau aggregation causes Alzheimer's Disease (AD). According to the researchers, their primary focus was on the MARK4 (microtubule affinity regulating kinase 4) enzyme and some mutation is occurring that induces dysfunction of this enzyme. It is phosphorylating tau at sites Ser 262 and Ser 356. As you may imagine, when tau is working correctly it serves as a component of the neuronal cytoskeleton. MARK4's job is to keep the microtubules from disassembling at a constant rate. Therefore, a mutation in this enzyme can have drastic effects on microtubule structure affinity, and intern, you begin to see the characteristic aggregation of these proteins that are seen in AD.  

Essentially what the team did was they introduced a genetically modified MARK4 enzyme into the fruit fly (drosophila) which had several chemical mutations via functional groups. What they noticed was that the mutated MARK4 caused an even greater effect of misfolding and aggregation of tau proteins. Not only that but it also made it a whole lot easier for the tau to aggregate in the first place. 

As for my thoughts, MARK4 is not just known to act on tau but other proteins as well. The researchers do mention this so it is very great research indeed but it almost feels as though what is the point. It is a smaller mechanism of action for tau aggregation due to hyperphosphorylation. I do believe this insight to be somewhat substantial but you also have to take into account that this was done in a fruit fly model. I would say that until the same results can be seen in mouse model neurons or if we can find this mechanism in post mortem AD patients, it is not a huge breakthrough in AD neurodegeneration. 

AD certainly is a difficult condition to study and unfortunately, no treatments have been found. There are just too many proteins that are affected and as I have come to realize, usually within neurological research, new questions arise that take into account a whole new brain structure or region and before you know it, questions are answered with more questions. 

My final thought is that since there is no clear treatment, would you be inclined to go through an AD risk-associated gene screening? 

Oba, T., Saito, T., Asada, A., Shimizu, S., Iijima, K. M., & Ando, K. (2020). Microtubule Affinity Regulating Kinase 4 with an Alzheimer’s disease-related mutation promotes tau accumulation and exacerbates neurodegeneration. Journal of Biological Chemistry, jbc.RA120.014420. https://doi.org/10.1074/jbc.RA120.014420