Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects

Abstract

WOREE syndrome caused by human germline biallelic mutations in WWOX is a neurodevelopmental disorder characterized by intractable epilepsy, severe developmental delay, ataxia and premature death at the age of 2–4 years. The underlying mechanisms of WWOX actions are poorly understood. In the current study, we show that specific neuronal deletion of murine Wwox produces phenotypes typical of the Wwox-null mutation leading to brain hyperexcitability, intractable epilepsy, ataxia and postnatal lethality. A significant decrease in transcript levels of genes involved in myelination was observed in mouse cortex and hippocampus. Wwox-mutant mice exhibited reduced maturation of oligodendrocytes, reduced myelinated axons and impaired axonal conductivity. Brain hyperexcitability and hypomyelination were also revealed in human brain organoids with a WWOX deletion. These findings provide cellular and molecular evidence for myelination defects and hyperexcitability in the WOREE syndrome linked to neuronal function of WWOX.

Modeling genetic epileptic encephalopathies using brain organoids

“…Since a major part of the phenotype was observed in the cortical areas of the COs, and since a recent paper has demonstrated a major role for WWOX in the cortex (Repudi et al , 2021 ), we decided to employ a cortex‐specific protocol and generate forebrain organoids (FOs) (Qian et al , 2016 , 2018 ). First, to validate reproducibility, we generated FOs from WSM F1 and WSM S5 and found comparable phenotypes for WSM COs (Appendix Figs S4F and G, and S5 ).…”

Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes

“…In a recent study, we found that conditional ablation of murine Wwox in either neural stem cells and progenitors (N-KO) or neuronal cells (S-KO mice) resulted in severe epilepsy, ataxia, and premature death at 3-4 weeks, recapitulating the phenotypes observed in the Wwox-null mice (Repudi et al, 2021). These results highlight the significant role of WWOX in neuronal function and prompted us to test whether restoring WWOX expression in the neuronal compartment of Wwox-null mice could reverse the observed phenotypes.…”

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 ].…”

“…Despite WWOX being a defined risk factor for AD [ 38 ], functional WWOX is needed to support the development of neural system and maintain normal neuronal physiology. Presence of dysfunctional WWOX, loss of WWOX, or excessive WWOX causes neurodegenerative diseases and neuronal death such as in AD [ 7 , 28 , 41 ], WOREE [ 60 , 61 , 62 , 63 , 69 , 70 , 71 , 72 , 73 ], sciatic nerve damage [ 42 , 96 ], retinal degeneration [ 68 ], and Parkinson’s disease [ 97 ].…”

“…During mouse embryonic development, WWOX protein is highly expressed in the neural crest-derived structures such as cranial and spinal ganglia, skin pigment cells, and mesenchyme in the head, indicating the potential involvement of WWOX in neuronal differentiation and maturation [69][70][71][72][73][74][75][76][77]. Genetic deficiency of WWOX/Wwox gene causes severe neural diseases (e.g., epilepsy, microcephaly, retinal degeneration, and ataxia), metabolic disorders (including lipid, cholesterol, and glucose metabolism), and early death in newborns [60][61][62][63][69][70][71][72][73][74][75]. 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].…”