TY - JOUR
T1 - Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects
AU - Repudi, Srinivasarao
AU - Steinberg, Daniel J.
AU - Elazar, Nimrod
AU - Breton, Vanessa L.
AU - Aquilino, Mark S.
AU - Saleem, Afifa
AU - Abu-Swai, Sara
AU - Vainshtein, Anna
AU - Eshed-Eisenbach, Yael
AU - Vijayaragavan, Bharath
AU - Behar, Oded
AU - Hanna, Jacob J.
AU - Peles, Elior
AU - Carlen, Peter L.
AU - Aqeilan, Rami I.
N1 - Publisher Copyright:
© 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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.
AB - 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.
KW - Brain organoids
KW - Electrophysiology
KW - Hypomyelination
KW - Seizures
KW - WOREE syndrome
UR - https://www.scopus.com/pages/publications/85110054495
U2 - 10.1093/brain/awab174
DO - 10.1093/brain/awab174
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C2 - 33914858
AN - SCOPUS:85110054495
SN - 0006-8950
VL - 144
SP - 3061
EP - 3077
JO - Brain
JF - Brain
IS - 10
ER -