Dual‐Specificity Tyrosine Phosphorylation‐Regulated Kinase‐1A (DYRK1A), A Master Regulatory Protein Involved in Down Syndrome Brain Alterations and Mental Disability, A Key Contributor to Neurodegenerative Disorders of Alzheimer's Disease and A Potential Therapeutic Target

Abstract

Down syndrome (DS) is the most frequent genetic disease characterized by several neuropathological features including alteration in neurogenesis, mental disability, cognitive impairments, learning-memory deficits and early onset of Alzheimer’s disease (AD). Over expression of chromosome 21 genes, localized in Down Syndrome Critical Region (DSCR), is the main cause of DS neuropathological features. We studied herein one of DSCR genes, DYRK1A (Dual-Specificity Tyrosine-Phosphorylation-Regulated Ki nase 1A), well-known Drosophila Mini-Brain gene, as a master regulator involved in DS neuropathological features and associated AD. DYRK1A is a central member of phosphorylation pathways regulating cell cycle and belongs to a family of Dual-Specificity Protein Kinases (DYRK kinases) playing key roles in central nervous system. DYRK1A regulates several transcriptional factors, such as CREB (cyclic-AMP response element-binding protein), NFAT (nuclear factor of activated T cells) and signaling pathways playing critical roles in brain functions. Significant associations were found between DYRK1A and regulation of cytoskeletal dynamics of actin, tubulin or microtubule-linked protein Tau, regulation of Tau phosphorylation, Amyloid Precursor Protein (APP) or Presenilin 1 (PS1), regulation of neurogenesis, synaptogenesis, and AD-like neurofibrillary tangles formation. Interestingly, normalization of DYRK1A overexpression by DYRK1A inhibitor, epigalloctechin-3-gallate (EGCG), rescues brain defects, restores cognitive impairments in DS trisomic and DYRK1A transgenic mouse models and DS patients,modulates Amyloid Precursor Protein (APP) cleavage and reduces cerebral amyloidosis in AD transgenic mouse models. DYRK1A inhibitors such as Har-mine, LeucettineL41, SM07883 successfully reduces Tau phosphorylation at multiple AD-related sites, rescues AD phenotypes in APP/PS1 mice and correct cognitive and memory deficits in AD animal models. These results indica tes DYRK1A inhibitors as effective treatments and identifies DYRK1A as a master regulatory protein involved in DS and AD neuropathological features suggestingDYRK1A as promising potential drug target for therapeutics and treatments of DS and AD. Down syndrome, Alzheimer’s disease, Mouse genetic models, Brain abnormalities, Cognitive deficits, Mental disabili -ty, DYRK1A inhibitors, DYRK1A therapeutic target