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

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3578-3589
Number of pages12
JournalOncotarget
Volume6
Issue number6
DOIs
Publication statusPublished - 2015

All Science Journal Classification (ASJC) codes

  • Oncology

Fingerprint Dive into the research topics of 'Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain'. Together they form a unique fingerprint.

Cite this