WWOX Phosphorylation, Signaling, and Role in Neurodegeneration

Abstract

Homozygous null mutation of tumor suppressor WWOX/Wwox gene leads to severe neural diseases, metabolic disorders and early death in the newborns of humans, mice and rats. WWOX is frequently downregulated in the hippocampi of patients with Alzheimer’s disease (AD). In vitro analysis revealed that knockdown of WWOX protein in neuroblastoma cells results in aggregation of TRAPPC6AΔ, TIAF1, amyloid β, and Tau in a sequential manner. Indeed, TRAPPC6AΔ and TIAF1, but not tau and amyloid β, aggregates are present in the brains of healthy mid-aged individuals. It is reasonable to assume that very slow activation of a protein aggregation cascade starts sequentially with TRAPPC6AΔ and TIAF1 aggregation at mid-ages, then caspase activation and APP de-phosphorylation and degradation, and final accumulation of amyloid β and Tau aggregates in the brains at greater than 70 years old. WWOX binds Tau-hyperphosphorylating enzymes (e.g., GSK-3β) and blocks their functions, thereby supporting neuronal survival and differentiation. As a neuronal protective hormone, 17β-estradiol (E2) binds WWOX at an NSYK motif in the C-terminal SDR (short-chain alcohol dehydrogenase/reductase) domain. In this review, we discuss how WWOX and E2 block protein aggregation during neurodegeneration, and how a 31-amino-acid zinc finger-like Zfra peptide restores memory loss in mice.

Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice

“…WWOX expression is relatively strong in human, rat and mouse neural tissues, and varies according to the location [19,34,53,61]. Notably, WWOX may interact with steroid hormone 17β-estradiol via its NSYK (Asn-Ser-Tyr-Lys) motif in the C-terminal short-chain alcohol dehydrogenase/reductase domain for neuroprotection [42]. Whether WWOX acts as a receptor for steroid hormones for initiating neuroprotective signaling pathways and promoting cerebellum development is unclear.…”

Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development

“…Despite the above studies, disease mechanisms by which loss of Wwox leads to WOREE-associated CNS alterations have not been fully understood yet. Different hypotheses have been proposed, including abnormal tau phosphorylation, mitochondrial dysfunction, altered cell differentiation, and neuronal apoptosis (Ramos and Aldaz, 2006;Aldaz et al, 2014;Liu et al, 2018). To investigate the impact of Wwox deficiency on human brain developmental processes, we performed brain histopathological analyses of the 21th week aborted fetus (II.3) with WOREE syndrome and identified abnormal architecture of the developing cerebral cortex.…”

The WWOX gene in brain development and pathology

“… 54 – 57 The hyperphosphorylated Tau molecules aggregate and form NTFs, thus restricting neurite outgrowth and preventing neuronal differentiation. 58 In addition, WWOX can also physically bind Tau protein by its SDR domain and stabilize it. 54 This regulation of Tau phosphorylation is important not only in the context of neurodegeneration, but also neuronal differentiation, where the Tau protein takes part in microtubule assembly and neurite outgrowth.…”

“…It has been found that WWOX prevents TPC6AΔ and TIAF1 aggregation by physically interacting with them. 58 In vitro stimulation with TGFβ results in the dissociation of WWOX from the complex and the initiation of the protein aggregation cascade. TPC6AΔ and Tau plaques were found in the brain cortex of WWOX knockout mice as early as in the first three weeks of life, and WWOX-depleted mouse embryonic fibroblasts (MEF) contain aggregates of TPC6AΔ, TIAF1, JNK1, and Tau tangles.…”