title: Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain.
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 Wwox gene 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 vitro analysis 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.
authors: Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.
authors: Jean-Yun
authors: JY
authors: Chang
authors: Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.
authors: Ming-Hui
authors: MH
authors: Lee
authors: Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.
authors: Sing-Ru
authors: SR
authors: Lin
authors: Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.
authors: Li-Yi
authors: LY
authors: Yang
authors: Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.
authors: H Sunny
authors: HS
authors: Sun
authors: Departments of Anatomy and Cell Biology, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.
authors: Chun-I
authors: CI
authors: Sze
authors: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, ROC.
authors: Qunying
authors: Q
authors: Hong
authors: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.|Center for Infectious Disease and Signaling Research, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.
authors: Yee-Shin
authors: YS
authors: Lin
authors: Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.
authors: Ying-Tsen
authors: YT
authors: Chou
authors: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.|Center for Infectious Disease and Signaling Research, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.|Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.
authors: Li-Jin
authors: LJ
authors: Hsu
authors: Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan, ROC.
authors: Ming-Shiou
authors: MS
authors: Jan
authors: Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors: Cheng-Xin
authors: CX
authors: Gong
authors: Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.|Center for Infectious Disease and Signaling Research, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.|Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan, ROC.|Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan, ROC.|Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors: Nan-Shan
authors: NS
authors: Chang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019556:COS Cells; D045744:Cell Line, Tumor; D002465:Cell Movement; D002522:Chlorocebus aethiops; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000378:metabolism*; D066263:Protein Aggregation, Pathological; D020033:Protein Isoforms; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D020033:Protein Isoforms; C514885:TRAPPC6A protein, mouse; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C428130:Wwox protein, mouse
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