WWOX and Its Binding Proteins in Neurodegeneration

Abstract

WW domain-containing oxidoreductase (WWOX) is known as one of the risk factors for Alzheimer’s disease (AD), a neurodegenerative disease. WWOX binds Tau via its C-terminal SDR domain and interacts with Tau phosphorylating enzymes ERK, JNK, and GSK-3β, and thereby limits AD progression. Loss of WWOX in newborns leads to severe neural diseases and early death. Gradual loss of WWOX protein in the hippocampus and cortex starting from middle age may slowly induce aggregation of a protein cascade that ultimately causes accumulation of extracellular amyloid beta plaques and intracellular tau tangles, along with reduction in inhibitory GABAergic interneurons, in AD patients over 70 years old. Age-related increases in pS14-WWOX accumulation in the brain promotes neuronal degeneration. Suppression of Ser14 phosphorylation by a small peptide Zfra leads to enhanced protein degradation, reduction in NF-κB-mediated inflammation, and restoration of memory loss in triple transgenic mice for AD. Intriguingly, tumor suppressors p53 and WWOX may counteract each other in vivo, which leads to upregulation of AD-related protein aggregation in the brain and lung. WWOX has numerous binding proteins. We reported that the stronger the binding between WWOX and its partners, the better the suppression of cancer growth and reduction in inflammation. In this regard, the stronger complex formation between WWOX and partners may provide a better blockade of AD progression. In this review, we describe whether and how WWOX and partner proteins control inflammatory response and protein aggregation and thereby limit AD progression.

WWOX Controls Cell Survival, Immune Response and Disease Progression by pY33 to pS14 Transition to Alternate Signaling Partners

“…WWOX and its binding proteins form a complicated signaling network which is needed for normal physiology and/or disease progression [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. WWOX was first discovered in 2000 [ 12 ].…”

“…A mitochondria-targeting region is located in the SDR domain. Both WW and SDR domains have their own specific protein-binding partners, as reviewed in a recent article [ 19 ]. The first WW domain (WW1) possesses two tryptophans and binds PPXY (e.g., PPPY) or LPXY motif [ 12 , 23 ] motif in the target proteins, where X is any amino acid.…”

“…The SDR domain has an NSYK (Asn-Ser-Tyr-Lys) motif, which binds sex steroid hormones androgen and estrogen [ 12 ]. The SDR domain also exhibits redox activity [ 35 , 36 , 37 ], and binds tau and GSK-3β to prevent tau hyperphosphorylation [ 19 , 38 , 39 , 40 ]. Whether the redox activity of SDR domain limits GSK-3β-mediated tau hyperphosphorylation and subsequent tau aggregation is unknown [ 38 , 40 ].…”

WWOX-Related Neurodevelopmental Disorders: Models and Future Perspectives

“…The association between WWOX and neurodegeneration has been studied for a long time but did not follow the "rodent-to-human" timeline that was described so far for the encephalopathies. As it has been extensively reviewed elsewhere [4,6,7,9], and for the sake of clarity, it is briefly described here with the main focus being the different models used through the years between studies and research groups.…”

“…The WW domain-containing oxidoreductase (WWOX) gene is gaining increasing attention for its possible role in both normal central nervous system (CNS) development, and its involvement in neurological diseases [2][3][4][5][6][7][8][9]. The WWOX gene was first discovered in the early 2000s due to its colocalization in the chromosomal common fragile site (CFS) FRA16D associated with cancer [10], which in turn led to thorough investigation of its role in tumor suppression, DNA damage response, metabolism, and cellular homeostasis, among other functions [11][12][13][14][15].…”