Vrk1 partial Knockdown in Mice Results in Reduced Brain Weight and Mild Motor Dysfunction, and Indicates Neuronal VRK1 Target Pathways

Hadar Vinograd-Byk,Ephrat Levy-Lahad,Paul Renbaum

doi:10.1038/s41598-018-29215-x

Hadar Vinograd-Byk, Ephrat Levy-Lahad + Show 1 more

Open Access

https://doi.org/10.1038/s41598-018-29215-x

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Abstract

Mutations in Vaccinia-related kinase 1 (VRK1) have emerged as a cause of severe neuronal phenotypes in human, including brain developmental defects and degeneration of spinal motor neurons, leading to Spinal Muscular Atrophy (SMA) or early onset Amyotrophic Lateral Sclerosis (ALS). Vrk1 gene-trap partial Knockout (KO) mice (Vrk1GT3/GT3), which express decreased levels of Vrk1, are sterile due to impaired gamete production. Here, we examined whether this mouse model also presents neuronal phenotypes. We found a 20–50% reduction in Vrk1 expression in neuronal tissues of the Vrk1GT3/GT3 mice, leading to mild neuronal phenotypes including significant but small reduction in brain mass and motor (rotarod) impairment. Analysis of gene expression in the Vrk1GT3/GT3 cortex predicts novel roles for VRK1 in neuronal pathways including neurotrophin signaling, axon guidance and pathways implicated in the pathogenesis of ALS. Together, our studies of the partial KO Vrk1 mice reveal that even moderately reduced levels of Vrk1 expression result in minor neurological impairment and indicate new neuronal pathways likely involving VRK1.

Highlights

The neurodegenerative disease associated with Vaccinia-related kinase 1 (VRK1) mutations manifests in all patients as progressive spinal motor neuron degeneration of early childhood to early adulthood onset
We looked at expression patterns of gene groups that might contribute to understanding the VRK1 phenotype, and performed a Gene Set Enrichment Analysis (GSEA)[19] on the entire set of expression data
VRK1 related disease is recessive, and as we have previously shown, R358X is subject to nonsense mediated decay and results in lack of VRK1 protein[8]

Summary

Introduction

The neurodegenerative disease associated with VRK1 mutations manifests in all patients as progressive spinal motor neuron degeneration of early childhood to early adulthood onset. Affected children suffer from spinal muscular atrophy (SMA)[7,8,9,10] or motor and sensory axonal neuropathy[9,11]. The disease has been clinically defined as distal SMA11 or early-onset amyotrophic lateral sclerosis (ALS)[12]

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