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

Srinivasarao Repudi, Daniel J. Steinberg, Nimrod Elazar, Vanessa L. Breton, Mark S. Aquilino, Afifa Saleem, Sara Abu-Swai, Anna Vainshtein, Yael Eshed-Eisenbach, Bharath Vijayaragavan, Oded Behar, Jacob J. Hanna, Elior Peles, Peter L. Carlen, Rami I. Aqeilan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

WWOX-related epileptic encephalopathy (WOREE) syndrome caused by human germline bi-allelic 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.

Original languageAmerican English
Pages (from-to)3061-3077
Number of pages17
JournalBrain
Volume144
Issue number10
DOIs
StatePublished - 1 Oct 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Keywords

  • Brain organoids
  • Electrophysiology
  • Hypomyelination
  • Seizures
  • WOREE syndrome

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