Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits. Issue 5 (20th September 2017)

• Record Type: Journal Article
• Authors: Stringer, Megan; Goodlett, Charles R.; Roper, Randall J.
• Is Part Of: Molecular genetics & genomic medicine. Volume 5:Issue 5(2017)
• Page Start: 451
• Page End: 465
• Publication Date: 2017-09-20
• Subjects: Down syndrome -- DYRK1A -- EGCG -- genotype‐phenotype correlation -- learning and memory -- Trisomy 21; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.334
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Overexpression of Dual‐specificity tyrosine‐phosphorylated regulated kinase 1A ( DYRK1A ), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS‐associated phenotypes have been largely unsuccessful. Epigallocatechin‐3‐gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS‐associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue‐specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue‐specific‐sensitive periods when Dyrk1a regulates cellular processes that shape the long‐term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes. Abstract : Overexpression and elevated activity of trisomic Dyrk1a are spatially and temporally specific in mouse models of DS, but systematic evidence is lacking. Some periods of elevated Dyrk1a may represent sensitive periods of developmental vulnerability for establishing long‐lasting DS structural and functional phenotypes. There is a paucity of evidence supporting the assertion that EGCG is an effective in vivo Dyrk1a inhibitor or that any beneficial effects of EGCG‐containing treatments are due to the inhibition of Dyrk1a.