WW domain-containing oxidoreductase (WWOX) (WWOX)

WW domain-containing oxidoreductase (WWOX) is a 46 kDa protein that functions as a tumor suppressor and a vital regulator of central nervous system (CNS) development. It is characterized by two N-terminal WW domains and a C-terminal short-chain dehydrogenase/reductase (SDR) domain, which allow it to act as a scaffold for various signaling proteins, including p53, Tau, and JNK. In the brain, WWOX is essential for neuronal differentiation, migration, and myelination; its loss leads to severe neurodevelopmental disorders, most notably WWOX-related epileptic encephalopathy (WOREE) syndrome and spinocerebellar ataxia type 12 (SCAR12). WWOX also plays a neuroprotective role in Alzheimer's disease by binding to Tau and preventing its hyperphosphorylation by kinases like GSK3β. Therapeutically, WWOX is a primary target for gene replacement therapies, such as the AAV9-based MZ-9138, which is designed to restore functional WWOX expression in neurons to treat WOREE syndrome. In oncology, WWOX is targeted to reactivate its tumor-suppressive and pro-apoptotic functions, which are often lost due to promoter hypermethylation or deletions at the FRA16D fragile site. Experimental agents like the Zfra peptide are being explored to modulate WWOX activity and mitigate protein aggregation in neurodegenerative conditions. However, the inherent instability of the FRA16D locus and the protein's potent pro-apoptotic effects present significant challenges for therapeutic development and safety.

Other names

WOX1FORSDR41C1Fragile site FRA16D oxidoreductaseWW domain-containing protein WWOXShort chain dehydrogenase/reductase family 41C member 1

Gene replacement therapy (AAV9-WWOX), upregulation of protein expression (Methotrexate), inhibition of tau hyperphosphorylation (Zfra peptide), induction of apoptosis (in cancer cells)