Role of WWOX and Zfra in limiting neurodegeneration
Abstract
Human and animal newborns with WWOX/Wwox gene deficiency suffer severe neural diseases, seizure, microcephaly, metabolic disorders, and early death. Neuronal heterotopia, which accounts for seizure, occurs in the newborns due to enhanced migration of cortical neurons to the epicortex. When tumor suppressor WWOX is Tyr33 phosphorylation, it strongly inhibits cancer growth in vitro and in vivo. When Tyr33 is de‐phosphorylated and Ser14 is phosphorylated, endogenous pS14‐WWOX is associated with enhanced growth of cancer stem cell spheres and solid tumors, and progression of neurodegeneration in patients with Alzheimer's disease (AD). We recently reported that a small zinc‐finger like Zfra peptide, e.g. Zfra1‐31 or 4–10, dramatically suppresses Ser14 phosphorylation in WWOX (>90% pS14‐WWOX), which leads to significant suppression of cancer growth and restoration of memory loss by blocking neurodegeneration in triple transgenic mice (3xTg) for AD. Also, when 3xTg mice received Zfra via tail vein injections at month 3, Zfra prevented age‐dependent loss of short‐term and long‐term memory in these mice. Zfra accelerates the degradation of aggregated proteins (e.g. amyloid beta) and activates a novel spleen non‐T/non‐B Hyal‐2+ CD3‐CD19‐lymphocyte, designated Z cells. Intringuingly, activated Z cells have a memory anticancer function, even though these cells have never gotten a chance encountering cancer cells or cancer cell antigens. Whether Z cells block neurodegeneration is unknown. Wwox heterozygous mice have an enhanced memory loss with age, compared to 3xTg mice. This is due, in part, to aggregation of a cascade of proteins, including initiators TRAPPC6AΔ, TIAF1, and SH2GLB2 (designated TTS) for causing amyloid beta and tau aggregation in the brain. In Wwox knockout mice, protein aggregates can be found in the cortex and hippocampus in 3 weeks after birth. In parallel, downregulation of WWOX protein in middle‐aged humans may lead to the TTS cascade of protein aggregation that allows formation of amyloid plaques and tau aggregation in old ages. Our study reveals an inhibitory role of WWOX and Zfra in suppressing neurodegeneration.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2019
- Source ID
- 10.1096/fasebj.2019.33.1_supplement.lb253
Entities
People
- Nan‐shan Chang
- Yu‐hao Lin
Organizations
- National Cheng Kung University
- National Science and Technology Council
- United States Department of Defense