Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration

Abstract

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 (Aβ) 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, Aβ, 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 β, 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.

Editorial: The role of STAT3 signaling pathway in tumor progression

“…WWOX overexpression binds JAK2 and suppresses STAT3 phosphorylation (9). WWOX not only restricts cancer progression but also limits neurodegeneration (10)(11)(12)(13). WWOX gene deficiency induces neural diseases, metabolic disorders and early death in newborn infants (11).…”

“…Whether and how the JAK1/STAT3 pathway participates in the neurodegenerative event and early death remains to be established. Downregulation of WWOX protein in the hippocampus and cortex in the mid-aged humans may lead to Alzheimer's disease during old age, which is due in part to aggregation of initiator proteins such as TRAPPC6AD, TIAF1 and SH3GLB2 (10,12,13). While STAT3 is also involved in neurodegeneration (2), we assume that downregulation of WWOX leads to aggregation of JAK1 or JKA2 that allows STAT3 to exert unwanted events in neurodegeneration.…”

Emerging concepts of myosin 18A isoform mechanobiology in organismal and immune system physiology, development, and function

“…92,93 TIAF1 aggregates with WWOX and p53 tumor suppressors may play differential roles in cancer pathogenesis and neural regeneration including Alzheimer's and Parkinson's disease. [94][95][96][97][98][99][100] The ability of MYO18A to convey migratory signals to the nucleus in three-dimensional matrix may sustain the invasion of malignant cells. 23 Considering these findings, the translational, mechanistic, and diagnostic role of MYO18A at the interface of cancer progression and neural degeneration must still be fully demonstrated.…”

Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration

“…We reported that when endogenous WWOX strongly binds intracellular protein partners in cancer cells, the cells cannot grow effectively in vivo [ 68 ]. When mice or cells are stimulated with the Zfra4-10 peptide, this peptide binds cell membrane hyaluronidase type II (Hyal-2) to activate the Hyal-2/WWOX/Smad4 signaling pathway [ 56 , 69 , 70 , 71 , 72 , 73 , 74 ]. The signaling activation leads to Smad4-mediated cell death or survival [ 69 , 70 , 71 , 72 , 73 , 74 ], cancer suppression [ 70 , 71 , 73 , 74 ], and restoration of memory loss in AD [ 71 ], depending upon the strength of signal activation.…”

“…Zfra4-10-mediated restoration of memory loss in triple transgenic mice for AD (3xTg) occurs via its inhibition of the aggregation of amyloid beta 42 (Aβ42), accelerating the degradation of aggregated proteins and blocking the activation of inflammatory NF-κB [ 71 ] ( Figure 3 ). Zfra4-10 prevents the age-dependent progression of AD-like symptoms in 3xTg mice [ 72 ]. Whether Zfra4-10 suppresses the expansion of inflammatory glial cells in the brain is unknown.…”