Identifying when and where a specific protein is elevated may be the key to improving the deficits observed in Down syndrome (DS), according to a review published in Molecular Genetics & Genomic Medicine. Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A) is a gene that is triplicated in DS, and has recently been touted as a target for drug development in DS. DYRK1A plays a critical role in the development of the central nervous system, and when its expression level is normalized, behavioral deficits are improved. So, why haven’t researchers administered a DYRK1A inhibitor to fix the deficits in DS? Well, that’s where things get tricky.
First, there are only a few DYRK1A inhibitors that are safe to use, and you may have already consumed one without knowing it. Epigallocatechin-3-gallate (EGCG) is the main polyphenol found in green tea, and inhibits DYRK1A in cells. However, studies that administer EGCG have yielded contrasting results, largely due to factors like the dose and timing of EGCG treatments. In addition, EGCG has been shown to inhibit numerous targets besides DYRK1A , thus, more specific inhibitors need to be developed.
Second, the “When” and “Where” of DYRK1A elevation during early life development is a mystery. The levels of DYRK1A are largely unknown between embryonic day 11.5 and 45 days of age in DS mouse models. This large age gap represents a crucial period of early brain development, and the authors hypothesize that the elevation of DYRK1A during this age range could be causing the abnormal phenotypes observed in DS. Understanding at what age, and in what brain regions DYRK1A is elevated will be essential for scientists to better administer DYRK1A inhibitors.
In summary, researchers are left with green tea that may (or may not) work, and a large gap in understanding when DYRK1A is elevated. While these findings may look dismal at first glance, scientists are currently testing improved DYRK1A inhibitors, and examining levels of DYRK1A during early development. If future studies can combine these two avenues of research, then DYRK1A inhibition may provide a means to improve the lives of individuals with DS.
Article: Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits
Published in Molecular Genetics & Genomic Medicine on September 20th, 2017