Gene Dosage-Dependent Association of DYRK1A With the Cytoskeleton in the Brain and Lymphocytes of Down Syndrome Patients

Abstract

The triplication of the DYRK1A gene encoding proline-directed serine/threonine kinase and located in the critical region of Down syndrome (DS) has been implicated in cognitive deficits and intellectual disability of individuals with DS. We investigated the effect of abnormal levels of this kinase on the cytoskeleton in brain and peripheral tissues of DS subjects. In DS tissues, the predictable ≈1.5-fold enhancement of the levels of DYRK1A protein was demonstrated. An association of DYRK1A with all 3 major cytoskeleton networks was identified using immunoprecipitation. We concentrated on the actin cytoskeleton because its association with DYRK1A was the most affected by the enzyme levels. As measured by co-immunoprecipitation in DS tissues, but not in fragile X lymphocytes, actin association with DYRK1A was reduced. This reduced association was dependent on the state of phosphorylation of cytoskeletal proteins and was present only in cells overproducing DYRK1A kinase; therefore, the effect was attributable to the DYRK1A gene dosage. Alterations of DYRK1A-actin assemblies were detected in newborn and infant groups, thereby linking DYRK1A overexpression with abnormal brain development of DS children. The identification of the actin cytoskeleton as one of cellular targets of DYRK1A action provides new insights into a gene-dosage-sensitive mechanism by which DYRK1A could contribute to the pathogenesis of DS. In addition, the presence of this DS-specific cytoskeleton anomaly in lymphocytes attests to the systemic nature of some features of DS. To our knowledge this is the first study conducted in human tissue that shows DYRK1A association with the cytoskeleton.

Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease

“…Among DS, AD, and controls, the levels of DYRK1A were highest in DS and lowest in AD, suggesting that the reduced formation of DYRK1Acytoskeleton complexes may be linked to abnormal levels of this kinase. As demonstrated by our studies in DS [21], DYRK1A action on cytoskeleton is regulated by an enzyme-dosage sensitive mechanism. Of special attention is the electrophoretic patterning of actin bands in immunoprecipitates.…”

“…The current study was initiated based on our published observations of DYRK1A association with the cytoskeleton and abnormalities of this association in the brain tissues and LCLs from DS patients [21]. Applying similar approaches to the brain, LCL, and blood-derived cells of AD patients led us to discover a candidate biomarker for early and near-definite diagnosis of AD.…”

“…Furthermore, the function of DYRK1A appears to be conserved in evolution; parallel RNAi screens in Drosophila cell lines identified Mnb as a regulator of the actin-based protrusions specifically in CNS-derived cell lines [20]. We have previously shown that DYRK1A is associated with cytoskeleton in a gene dosage-sensitive manner [21]. Both the brain tissue and immortalized lymphocytes of DS patients displayed a significant reduction in the yield of all major cytoskeletal proteins co-immunoprecipitated with DYRK1A antibodies.…”

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

“…46,47 In addition, DYRK1A interacts with the microtubule and actin cytoskeletal networks to regulate neurite outgrowth and synaptogenesis. [48][49][50] Through these mechanisms, haploinsuffciency of DYRK1A presumably leads to augmented neuronal precursor proliferation and apoptosis, decreased neurogenesis and abnormal neuritogenesis. A molecular mechanism that may explain the suppressed appetite in patients with DYRK1A-associated ID has recently been elucidated in flies and mice.…”

Modeling Down syndrome in animals from the early stage to the 4.0 models and next

“…Impact of DYRK1A in neuronal activity was visualized by reduced spontaneous neuronal activity, increase in the amplitude of miniature excitatory postsynaptic currents (mEPSCs) in prefrontal cortex pyramidal neurons and by the characterization of modifications in the hippocampal longterm potentiation (LTP) and long-term depression (LTD) in mouse models overexpressing Dyrk1a (Ahn et al, 2006, Martinez de Lagran et al, 2012, Thomazeau et al, 2014. Those phenotypes have been linked to impact of DYRK1A on the cytoskeletal machinery via phosphorylation of proteins implicated in actin and microtubules assembly (Colón-Ramos, 2009, Dowjat et al, 2012, Martinez de Lagran et al, 2012, Park et al, 2012, Aranda et al, 2008, Kaczmarski et al, 2014, Liu et al, 2009, Ori-McKenney et al, 2016, Scales et al, 2009, Ryoo et al, 2008, Woods et al, 2001. Neuronal function was also found to be affected by DYRK1A through impact on expression or translation of key synaptic proteins such as neuroligin1, TrkBT1, Bdnf, AchE-S, and AchE-R (Toiber et al, 2010), on the activity of key transcription factors (NFAT and CREB) or proteins (Gsk3b, Ras, Raf and MEK1) implicated in synaptic plasticity (Arron et al, 2006, Yang et al, 2001, Song et al, 2015, Kelly and Rahmani, 2005, and on its interaction with key proteins involved in either neurotransmitter release or post-synaptic receptor trafficking.…”