Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration.

When WWOX is downregulated in middle age, aggregation of a protein cascade, including TRAPPC6AΔ (TPC6AΔ), TIAF1, and SH3GLB2, may start to occur, and the event lasts more than 30 years, which results in amyloid precursor protein (APP) degradation, amyloid beta (Aß) generation, and neurodegeneration, as shown in Alzheimer's disease (AD). Here, by treating neuroblastoma SK-N-SH cells with neurotoxin MPP+, upregulation and aggregation of TPC6AΔ, along with aggregation of TIAF1, SH3GLB2, Aß, and tau, occurred. MPP+ is an inducer of Parkinson's disease (PD), suggesting that TPC6AΔ is a common initiator for AD and PD pathogenesis. Zfra, a 31-amino-acid zinc finger-like WWOX-binding protein, is known to restore memory deficits in 9-month-old triple-transgenic (3xTg) mice by blocking the aggregation of TPC6AΔ, SH3GLB2, tau, and amyloid ß, as well as inflammatory NF-κB activation. The Zfra4-10 peptide exerted a strong potency in preventing memory loss during the aging of 3-month-old 3xTg mice up to 9 months, as determined by a novel object recognition task (ORT) and Morris water maize analysis. Compared to age-matched wild type mice, 11-month-old Wwox heterozygous mice exhibited memory loss, and this correlates with pT12-WWOX aggregation in the cortex. Together, aggregation of pT12-WWOX may link to TPC6AΔ aggregation for AD progression, with TPC6AΔ aggregation being a common initiator for AD and PD progression.

HYAL-2-WWOX-SMAD4 Signaling in Cell Death and Anticancer Response.

Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-ß) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2-WWOX-SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2-WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2-WWOX-SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3- CD19- Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2-WWOX-SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2-WWOX-SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response.

WW domain-containing oxidoreductase in neuronal injury and neurological diseases.

The human and mouse WWOX/Wwox gene encodes a candidate tumor suppressor WW domain-containing oxidoreductase protein. This gene is located on a common fragile site FRA16D. WWOX participates in a variety of cellular events and acts as a transducer in the many signal pathways, including TNF, chemotherapeutic drugs, UV irradiation, Wnt, TGF-ß, C1q, Hyal-2, sex steroid hormones, and others. While transiently overexpressed WWOX restricts relocation of transcription factors to the nucleus for suppressing cancer survival, physiological relevance of this regard in vivo has not been confirmed. Unlike many tumor suppressor genes, mutation of WWOX is rare, raising a question whether WWOX is a driver for cancer initiation. WWOX/Wwox was initially shown to play a crucial role in neural development and in the pathogenesis of Alzheimer's disease and neuronal injury. Later on, WWOX/Wwox was shown to participate in the development of epilepsy, mental retardation, and brain developmental defects in mice, rats and humans. Up to date, most of the research and review articles have focused on the involvement of WWOX in cancer. Here, we review the role of WWOX in neural injury and neurological diseases, and provide perspectives for the WWOX-regulated neurodegeneration.