Research Papers: Gerotarget (Focus on Aging):
Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain
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Jean-Yun Chang1, Ming-Hui Lee1, Sing-Ru Lin1, Li-Yi Yang1, H. Sunny Sun1, Chun-I Sze2, Qunying Hong3, Yee-Shin Lin4,5, Ying-Tsen Chou6, Li-Jin Hsu4,5,7, Ming-Shiou Jan8, Cheng-Xin Gong9, Nan-Shan Chang1,5,6,8,10
1Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, ROC
2Departments of Anatomy and Cell Biology, National Cheng Kung University Medical College, Tainan, Taiwan, ROC
3Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, PRC
4Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan, ROC
5Center for Infectious Disease and Signaling Research, National Cheng Kung University Medical College, Tainan, Taiwan, ROC
6Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan, ROC
7Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University Medical College, Tainan, Taiwan, ROC
8Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan, ROC
9Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan, ROC
10Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
Nan-Shan Chang, e-mail: [email protected]
Li-Jin Hsu, e-mail: [email protected]
Chun-I Sze, e-mail: [email protected]
Keywords: Alzheimer's disease, protein aggregation, hippocampus, amyloid beta, TIAF1, TRAPPC6A, WWOX, WOX1
Received: November 12, 2014 Accepted: December 08, 2014 Published: February 19, 2015
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.
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