A recent large genome-wide association meta-analysis revealed that the human WWOX gene is regarded as one of the five newly identified risk factors for Alzheimer’s disease (AD). However, this study did not functionally characterize how WWOX protein deficiency affects AD initiation, progression and neurodegeneration. In this review, evidence and perspectives are provided regarding how WWOX works in limiting neurodegeneration. Firstly, loss of WWOX/Wwox gene leads to severe neural diseases with degeneration, metabolic disorder and early death in the newborns. Downregulation of pY33-WWOX may start at middle ages, and this leads to slow aggregation of a cascade of proteins, namely TRAPPC6A[Formula: see text], TIAF1 and SH3GLB2, that leads to amyloid-beta (A[Formula: see text]) formation and tau tangle formation in old-aged AD patients. Secondly, functional antagonism between tumor suppressors p53 and WWOX may occur in vivo, in which p53-mediated inflammation is blocked by WWOX. Loss of balance in the functional antagonism leads to aggregation of pathogenic proteins for AD such as tau and A[Formula: see text] in the brain cortex and hippocampus. Thirdly, downregulation of pY33-WWOX is accompanied by upregulation of pS14-WWOX. The event frequently correlates with enhanced AD progression and cancer cell growth in vivo. A small peptide Zfra4-10 dramatically suppresses pS14-WWOX and restores memory loss in triple transgenic (3xTg) mice, and inhibits cancer growth in mice as well. Finally, a supporting scenario is that WWOX deficiency induces enhanced cell migration and loss of cell-to-cell recognition. This allows the generation of neuronal heterotopia and associated epileptic seizure in WWOX-deficient newborn patients.
As a tumor suppressor, WWOX is a recently defined risk factor for Alzheimer's disease (AD). WWOX limits AD progression due, in part, to its suppression of tau tangle formation by direct binding of tau and tau‐phosphorylating enzymes. Deficiency of WWOX leads to severe neural diseases such as epileptic encephalopathy, microcephaly, and early death in newborns. During AD progression, pS14‐WWOX and aggregated TRAPPC6AΔ, TIAF1, SH3GLB2, tau and amyloid beta are accumulated in the auditory cortex and hippocampal CA1, CA3, or DG areas of the brains of triple transgenic (3xTg) mice and heterozygous Wwox mice. Here, we determined that suppression of pS14‐WWOX by a zinc finger‐like peptide Zfra4‐10 leads to clearup of tau tangles and amyloid plaques, reduced activation of inflammatory microglia and astrocytes, downregulated epilepsy‐related REST protein expression, and restored memory loss in 3xTg mice and heterozygous Wwox mice. Notably, the Zfra action is due in part to its activated Hyal‐2+ spleen Z lymphocytes. When purified activated Z cells were transferred to recipient 3xTg mice, these mice strongly resisted Pentylenetetrazole (PTZ)‐induced seizure. Whether Z cells block AD progression are being determined in our laboratory. There are 2% Z cells in the brain. Transfer of brain Z cells to recipient mice also confers resistance to PTZ‐induced seizure. Taken together, both Zfra peptide and Z cells are expected to be of great therapeutic potential for AD patients or seizure‐stricken WWOX‐deficient newborns.
As a tumor suppressor, WWOX is a recently defined risk factor for Alzheimer’s disease (AD). WWOX limits AD progression due, in part, to its suppression of tau tangle formation by direct binding of tau and tau‐phosphorylating enzymes. Deficiency of WWOX leads to severe neural diseases, including epileptic encephalopathy, microcephaly, intractable seizures and developmental delay, and early death in human and animal newborns. Wwox knockout mice, which survive in less than 1 month, display spontaneous and audiogenic seizures and rapid formation of tau and amyloid aggregates in the brain in less than 3 weeks after birth. During AD progression in humans and mice, pS14‐WWOX is shown to accumulate in the brain hippocampus and cortex. Suppression of pS14‐WWOX by a short synthetic peptide Zfra (zinc finger‐like protein that regulates apoptosis) leads to clear up of tau tangles and amyloid plaques, and restoration of memory loss in triple transgenic mice for AD. Here, we determined that when Wwox wild type and heterozygous mice were pre‐injected with a Zfra4–10 peptide via tail veins, these mice resisted pentylenetetrazone (PTZ)‐induced seizure. Mechanistically, Zfra significantly suppressed pS14‐WWOX in the auditory cortex and hippocampal CA1, CA3, or DG areas. Zfra blocked PTZ‐induced activation of inflammatory microglia and astrocytes in mouse hippocampus. Also, Zfra significantly blocked the expression of RE1‐silencing transcription factor (REST) (>90%), which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy. Together, our observations suggest that Zfra peptide is a potent agent in mitigating epileptic seizure caused by WWOX deficiency. Support or Funding Information Ministry of Science and Technology, Taiwan, National Health Research Institute, Taiwan, and Department of Defense, USA.
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