Abu-Swai, S. | bioRxiv Science

bioRxiv2025

WWOX deficiency uncovers a cell-autonomous mechanism impairing myelin repair

Remyelination is essential for neuronal function and plasticity, and its failure contributes to multiple sclerosis (MS) and other neurodegenerative disorders. Yet, the molecular programs governing oligodendrocyte precursor cell (OPC) differentiation and remyelination remain incompletely defined. Here, we identify the WW domain-containing oxidoreductase (WWOX) as a critical cell-autonomous regulator of oligodendrocyte differentiation and myelin repair. Reanalysis of single-nucleus RNA sequencing from MS lesions revealed WWOX as one of the most significantly dysregulated oligodendroglial genes. Conditional deletion of Wwox in oligodendroglia impaired OPC differentiation, favouring aberrant proliferation and blocking myelin regeneration after cuprizone-induced demyelination. Single-nucleus transcriptomics confirmed profound transcriptional reprogramming in WWOX-deficient oligodendroglia during remyelination, with enrichment of WNT and TGF{beta} signalling and cell cycle programs. Mechanistically, WWOX physically interacts with the master transcription factor SOX10 via its WW1 domain, stabilising SOX10 protein and sustaining its downstream myelin gene network. Loss of WWOX reduced SOX10 stability and activity, providing a direct mechanistic link to defective OPC differentiation. Together, our findings uncover WWOX as an essential orchestrator of remyelination and position the WWOX-SOX10 axis as a promising therapeutic target for enhancing myelin repair in MS and related demyelinating disorders.

neuroscience↗

bioRxiv2021

Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes

WW domain-containing oxidoreductase (WWOX) is an emerging neural gene regulating homeostasis of the central nervous system. Germline biallelic mutations in WWOX cause WWOX-related epileptic encephalopathy (WOREE) syndrome and spinocerebellar ataxia, and autosomal recessive 12 (SCAR12), two devastating neurodevelopmental disorders with highly heterogenous clinical outcomes, the most common being severe epileptic encephalopathy and profound global developmental delay. We recently demonstrated that neuronal ablation of murine Wwox recapitulates phenotypes of Wwox-null mice leading to intractable epilepsy, hypomyelination and postnatal lethality. Here, we designed and produced an adeno-associated viral vector harboring murine Wwox or human WWOX cDNA and driven by the human neuronal Synapsin I promoter (AAV-SynI-WWOX). Testing the efficacy of AAV-SynI-WWOX delivery in Wwox null mice demonstrated that specific neuronal restoration of WWOX expression rescued brain hyperexcitability and seizures, hypoglycemia, and myelination deficits as well as the premature lethality of Wwox-null mice. These findings provide a proof-of-concept for WWOX gene therapy as a promising approach to curing children with WOREE and SCAR12.

neuroscience↗