Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain

Jean Yun Chang, Ming Hui Lee, Sing Ru Lin, Li Yi Yang, H. Sunny Sun, Chun I. Sze, Qunying Hong, Yee Shin Lin, Ying Tsen Chou, Li Jin Hsu, Ming Shiou Jan, Cheng Xin Gong, Nan Shan Chang

研究成果: Article

15 引文 (Scopus)

摘要

Tumor suppressor WWOX is involved in the progression of cancer and neurodegeneration. Here, we examined whether protein aggregation occurs in the brain of nondemented, middle-aged humans and whether this is associated with WWOX downregulation. We isolated an N-terminal internal deletion isoform, TPC6AΔ, derived from alternative splicing of the TRAPPC6A(TPC6A) gene transcript. TPC6AΔ proteins are present as aggregates or plaques in the extracellular matrix of the brain such as in the cortex. Filter retardation assays revealed that aggregate formation of TPC6AΔ occurs preceding Aβ generation in the hippocampi of middle-aged postmortem normal humans. In a Wwoxgene knockout mouse model, we showed the plaques of pT181-Tau and TPC6AΔ in the cortex and hippocampus in 3-week-old mice, suggesting a role of WWOX in limiting TPC6AΔ aggregation. To support this hypothesis, in vitroanalysis revealed that TGF-β1 induces dissociation of the ectopic complex of TPC6AΔ and WWOX in cells, and then TPC6AΔ undergoes Ser35 phosphorylation-dependent polymerization and induces caspase 3 activation and Aβ production. Similarly, knockdown of WWOX by siRNA resulted in dramatic aggregation of TPC6AΔ. Together, when WWOX is downregulated, TPC6AΔ is phosphorylated at Ser35 and becomes aggregated for causing caspase activation that leads to Tau aggregation and Aβ formation.

原文English
頁(從 - 到)3578-3589
頁數12
期刊Oncotarget
6
發行號6
DOIs
出版狀態Published - 2015 一月 1

指紋

Protein Transport
Hippocampus
Down-Regulation
Brain
Alternative Splicing
Caspases
Knockout Mice
Caspase 3
Polymerization
Small Interfering RNA
Extracellular Matrix
Neoplasms
Protein Isoforms
Proteins
Phosphorylation
Genes

All Science Journal Classification (ASJC) codes

  • Oncology

引用此文

Chang, Jean Yun ; Lee, Ming Hui ; Lin, Sing Ru ; Yang, Li Yi ; Sunny Sun, H. ; Sze, Chun I. ; Hong, Qunying ; Lin, Yee Shin ; Chou, Ying Tsen ; Hsu, Li Jin ; Jan, Ming Shiou ; Gong, Cheng Xin ; Chang, Nan Shan. / Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain. 於: Oncotarget. 2015 ; 卷 6, 編號 6. 頁 3578-3589.
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abstract = "Tumor suppressor WWOX is involved in the progression of cancer and neurodegeneration. Here, we examined whether protein aggregation occurs in the brain of nondemented, middle-aged humans and whether this is associated with WWOX downregulation. We isolated an N-terminal internal deletion isoform, TPC6AΔ, derived from alternative splicing of the TRAPPC6A(TPC6A) gene transcript. TPC6AΔ proteins are present as aggregates or plaques in the extracellular matrix of the brain such as in the cortex. Filter retardation assays revealed that aggregate formation of TPC6AΔ occurs preceding Aβ generation in the hippocampi of middle-aged postmortem normal humans. In a Wwoxgene knockout mouse model, we showed the plaques of pT181-Tau and TPC6AΔ in the cortex and hippocampus in 3-week-old mice, suggesting a role of WWOX in limiting TPC6AΔ aggregation. To support this hypothesis, in vitroanalysis revealed that TGF-β1 induces dissociation of the ectopic complex of TPC6AΔ and WWOX in cells, and then TPC6AΔ undergoes Ser35 phosphorylation-dependent polymerization and induces caspase 3 activation and Aβ production. Similarly, knockdown of WWOX by siRNA resulted in dramatic aggregation of TPC6AΔ. Together, when WWOX is downregulated, TPC6AΔ is phosphorylated at Ser35 and becomes aggregated for causing caspase activation that leads to Tau aggregation and Aβ formation.",
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Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain. / Chang, Jean Yun; Lee, Ming Hui; Lin, Sing Ru; Yang, Li Yi; Sunny Sun, H.; Sze, Chun I.; Hong, Qunying; Lin, Yee Shin; Chou, Ying Tsen; Hsu, Li Jin; Jan, Ming Shiou; Gong, Cheng Xin; Chang, Nan Shan.

於: Oncotarget, 卷 6, 編號 6, 01.01.2015, p. 3578-3589.

研究成果: Article

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AU - Chang, Jean Yun

AU - Lee, Ming Hui

AU - Lin, Sing Ru

AU - Yang, Li Yi

AU - Sunny Sun, H.

AU - Sze, Chun I.

AU - Hong, Qunying

AU - Lin, Yee Shin

AU - Chou, Ying Tsen

AU - Hsu, Li Jin

AU - Jan, Ming Shiou

AU - Gong, Cheng Xin

AU - Chang, Nan Shan

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