Overexpressed Down Syndrome Cell Adhesion Molecule (DSCAM) Deregulates P21-Activated Kinase (PAK) Activity in an In Vitro Neuronal Model of Down Syndrome: Consequences on Cell Process Formation and Extension

Abstract

In humans, Down syndrome (DS) is caused by the presence of an extra copy of autosome 21. The most striking finding in DS patients is intellectual disability and the onset of Alzheimer's disease (AD)-like neuropathology in adulthood. Gene overdose is most likely to underlie both developmental impairments, as well as altered neuronal function in DS. Lately, the disruption of cellular signaling and regulatory pathways has been implicated in DS pathophysiology, and many of such pathways may represent common targets for diverse DS-related genes, which could in turn represent attractive therapeutical targets. In this regard, one DS-related gene Down Syndrome Cell Adhesion Molecule (DSCAM), has important functions in neuronal proliferation, maturation, and synaptogenesis. p21-associated kinases (PAKs) appear as a most interesting possibility for study, as DSCAM is known to regulate the PAKs pathway. Hence, in DS, overexpressed DSCAM could deregulate PAKs activity and affect signaling pathways that regulate synaptic plasticity such as dendritic spine dynamics and axon guidance and growth. In the present work, we used an immortalized cell line derived from the cerebral cortex of an animal model of DS such as the trisomy 16 (Ts16) fetal mouse (named CTb), and a similar cell line established from a normal littermate (named CNh), to study the effect of DSCAM in the PAKs pathway. The present study shows that DSCAM is overexpressed in CTb cells by approximately twofold, compared to CNh cells. Congruently, PAK1, as well as its downstream effectors LIMK and cofilin, stay phosphorylated for longer periods after DSCAM activation in the CTb cells, leading to an altered actin dynamics, expressed as an increased basal F/G ratio and reduced neurite growth, in the trisomic condition. The present work presents the correlation between DSCAM gene overexpression and a dysregulation of the PAK pathway, resulting in altered morphological parameters of neuronal plasticity in the trisomic cell line, namely decreased number and length of processes.

Dscam1 promotes blood cell survival inDrosophila melanogasterthrough a dual role in blood cells and neurons

“…Dock is required for Dscam1 functions in the nervous system such as axon guidance and dendritogenesis (6,48), through direct interaction with the Dscam1 cytoplasmic domain (6,37,48). Dock in turn binds and activates the p21-activated kinase Pak (37,49,50), an effector of the Rho GTPases Cdc42 and Rac (46,48,49,51) Our work reveals an unexpected role of Dscam1/Dock signaling in promoting anti-apoptotic survival of Drosophila hemocytes. This activity has not been described previously, although it has e.g.…”

Synaptic actin stabilization protein loss in Down syndrome and Alzheimer disease

“…DS individuals tend to exhibit elevated DSCAM levels, particularly in cortical neurons . Interestingly, DSCAM overexpression in an immortalized cell line from a DS mouse model resulted in aberrant netrin 1‐induced PAK1 phosphorylation but levels of PAK1‐3 isoforms were unaffected . This suggests that elevated DSCAM levels in DS could influence PAK activity without an effect on PAK protein content.…”

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

“…The role of Kcnj6 in DS cognitive deficit was further evidenced by the rescue of the cognitive deficits observed in the Ts65Dn model when crossed with Kcnj6 +/mice (Kleschevnikov et al, 2017). Other candidate genes present within the DSCR are the PCP4 gene coding for the Purkinje cell protein 4, a small calmodulin-binding protein whose overexpression in TgPCP4 mice induces premature neuronal differentiation (Mouton-Liger et al, 2011, Mouton-Liger et al, 2014 while its normalization in the brain of Dp1Rhr trisomic mice rescues the cilia dysfunction observed in this model (Raveau et al, 2017) and DSCAM (Down syndrome cell adhesion molecule), a cell adhesion molecule is responsible for the alteration of actin dynamics in a neuronal cell line of Dp16 mice (Pérez-Núñez et al, 2016).…”