WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

Abstract

The WWOX gene was initially discovered as a putative tumor suppressor. More recently, its association with multiple central nervous system (CNS) pathologies has been recognized. WWOX biallelic germline pathogenic variants have been implicated in spinocerebellar ataxia type 12 (SCAR12; MIM:614322) and in early infantile epileptic encephalopathy (EIEE28; MIM:616211). WWOX germline copy number variants have also been associated with autism spectrum disorder (ASD). All identified germline genomic variants lead to partial or complete loss of WWOX function. Importantly, large-scale genome-wide association studies have also identified WWOX as a risk gene for common neurodegenerative conditions such as Alzheimer’s disease (AD) and multiple sclerosis (MS). Thus, the spectrum of CNS disorders associated with WWOX is broad and heterogeneous, and there is little understanding of potential mechanisms at play. Exploration of gene expression databases indicates that WWOX expression is comparatively higher in the human cerebellar cortex than in other CNS structures. However, RNA in-situ hybridization data from the Allen Mouse Brain Atlas show that specific regions of the basolateral amygdala (BLA), the medial entorhinal cortex (EC), and deep layers of the isocortex can be singled out as brain regions with specific higher levels of Wwox expression. These observations are in close agreement with single-cell RNA-seq data which indicate that neurons from the medial entorhinal cortex, Layer 5 from the frontal cortex as well as GABAergic basket cells and granule cells from cerebellar cortex are the specific neuronal subtypes that display the highest Wwox expression levels. Importantly, the brain regions and cell types in which WWOX is most abundantly expressed, such as the EC and BLA, are intimately linked to pathologies and syndromic conditions in turn associated with this gene, such as epilepsy, intellectual disability, ASD, and AD. Higher Wwox expression in interneurons and granule cells from cerebellum points to a direct link to the described cerebellar ataxia in cases of WWOX loss of function. We now know that total or partial impairment of WWOX function results in a wide and heterogeneous variety of neurodegenerative conditions for which the specific molecular mechanisms remain to be deciphered. Nevertheless, these observations indicate an important functional role for WWOX in normal development and function of the CNS. Evidence also indicates that disruption of WWOX expression at the gene or protein level in CNS has significant deleterious consequences.

Neonatal neuronal WWOX gene therapy rescuesWwoxnull phenotypes

“…9,10 Of particular interest is WOREE syndrome, a devastating complex neurological disease causing premature death with a median survival of 1-4 years. 9,10 WOREE children are refractory to the current antiepileptic drugs (AEDs) hence challenging the medical and scientific communities to develop new therapeutic strategies. We believe that delivering AAV9-WWOX into the brain of WOREE syndrome patients could be a novel gene therapy approach that would help these patients.…”

“…These findings might suggest that WWOX's proposed role in regulating autism [9][10][11]33,34 and perhaps other behavior-associated disorders is driven by proper neuronal function of WWOX.…”

Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview

“…A detailed analysis of human WWOX mRNA expression in the CNS has been recently reviewed elsewhere [ 34 ]. In brief, WWOX mRNA expression is prominent during the early embryonic stages and decreases gradually with fetal development [ 34 ]. Upon birth, there is an increase in WWOX expression that remains stable throughout adulthood in all brain regions.…”

WWOX and Its Binding Proteins in Neurodegeneration

“…Chronic inflammation in the brain occurs due to increased activation of GSK-3β for causing epileptic seizure, and upregulation of microglia cells and astrocytes and reduced GABG-ergic inhibitory interneurons in the brain cortex and hippocampus [ 61 ]. Together, WWOX deficiency in newborns suffer the disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), early infantile epileptic encephalopathy (EIEE), and WWOX -related epileptic encephalopathy (WOREE syndrome) [ 60 , 61 , 62 , 63 , 69 , 70 , 71 , 72 , 73 ]. WWOX controls neuronal differentiation, and that loss of WWOX induces activation of GSK-3β that contributes to neurodegeneration [ 49 ].…”