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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 (Aβ) generation, and neurodegeneration,...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739312/ https://www.ncbi.nlm.nih.gov/pubmed/36498839 http://dx.doi.org/10.3390/ijms232314510 |
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author | Lin, Yu-Hao Shih, Yao-Hsiang Yap, Ye Vone Chen, Yen-Wei Kuo, Hsiang-Lin Liu, Tsung-Yun Hsu, Li-Jin Kuo, Yu-Min Chang, Nan-Shan |
author_facet | Lin, Yu-Hao Shih, Yao-Hsiang Yap, Ye Vone Chen, Yen-Wei Kuo, Hsiang-Lin Liu, Tsung-Yun Hsu, Li-Jin Kuo, Yu-Min Chang, Nan-Shan |
author_sort | Lin, Yu-Hao |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9739312 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97393122022-12-11 Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration Lin, Yu-Hao Shih, Yao-Hsiang Yap, Ye Vone Chen, Yen-Wei Kuo, Hsiang-Lin Liu, Tsung-Yun Hsu, Li-Jin Kuo, Yu-Min Chang, Nan-Shan Int J Mol Sci Article 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. MDPI 2022-11-22 /pmc/articles/PMC9739312/ /pubmed/36498839 http://dx.doi.org/10.3390/ijms232314510 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lin, Yu-Hao Shih, Yao-Hsiang Yap, Ye Vone Chen, Yen-Wei Kuo, Hsiang-Lin Liu, Tsung-Yun Hsu, Li-Jin Kuo, Yu-Min Chang, Nan-Shan Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration |
title | Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration |
title_full | Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration |
title_fullStr | Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration |
title_full_unstemmed | Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration |
title_short | Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration |
title_sort | zfra inhibits the trappc6aδ-initiated pathway of neurodegeneration |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739312/ https://www.ncbi.nlm.nih.gov/pubmed/36498839 http://dx.doi.org/10.3390/ijms232314510 |
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