Phosphorylation of Amphiphysin I by Minibrain Kinase/Dual-specificity Tyrosine Phosphorylation-regulated Kinase, a Kinase Implicated in Down Syndrome

Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer’s?

“…The higher concentration of harmine 1a required to block autophosphorylation indicates that this is likely not the major mechanism of DYRK1A inhibition in vivo. 49 Furthermore, in 2011, harmine and several other analogues were assayed for their ability to inhibit DYRK1A mediated phosphorylation of AD relevant protein tau (4R2N Tau) at Ser396 in vitro, a site which has been shown to be phosphorylated in NFTs. 39 Harmine was found to inhibit direct phosphorylation of tau by DYRK1A at Ser396 with an IC 50 of 700 nM.…”

“…48 Synaptic proteins Amph 1, Dynamin 1, and Synaptojanin, involved in the regulation of endocytosis, are also subject to DYRK1A mediated phosphorylation, which may alter the number, size, and morphology of dendritic spines, thereby reducing synaptic plasticity. 49 Furthermore, research suggests a role for DYRK1A 51 Collectively, a large body of evidence now exists to support critical roles for DYRK1A in facilitating neurodegeneration and dementia through various pathways. Inhibition of DYRK1A functioning should theoretically mitigate multiple processes underlying the progression of neurodegeneration, particularly in Alzheimer's disease for which key DYRK1A targets (tau protein, amyloid precursor protein, presenilin 1) point to clear mechanisms through which elevated DYRK1A activity may be promoting disease progression.…”

Two key genes closely implicated with the neuropathological characteristics in Down syndrome: DYRK1A and RCAN1

“…Second, DYRK1A targets many endocytic proteins, such as dynamin 1 and amphiphysin 1. By phosphorylation, DYRK1A regulates the assembly of endocytic complexes, which are composed of endophilin 1 and Grb2, suggesting that DYRK1A is closely associated with the endocytic pathway (35,36). Moreover, DYRK1A phosphorylates eukaryotic protein synthesis initiation factor 2B epsilon (eIF2Bε) (37) and glycogen synthase (38), indicating that DYRK1A may affect the basic cellular metabolism.…”

Chapter 4 Alzheimer's Disease in Adults with Down Syndrome

“…For example, transgenic mice carrying an extra human minibrain-kinase gene show defects in learning and memory (Smith & Rubin, 1997;. Experimental studies of hippocampal cells overexpressing minibrainkinase have shown large increases in apoptotic cell death and reduction in neuronal differentiation (Park, Yang, Yoon, & Chung, 2007;Wisniewski, 1990), and this mechanism may underlie the altered neuronal plasticity and intellectual disability observed in Down syndrome (Murakami et al, 2006). Beta-amyloid deposition in neuritic plaques and in the wall of brain vessels, neurofibrillary degeneration and neuronal loss are major neuropathological hallmarks of Alzheimer's disease.…”