Molecular alterations of TRAPPC6A during trafficking

Abnormal protein aggregation is a common cause for neurodegeneration. TRAPPC6A (TPC6A) is a component of the transport protein particle (TRAPP) complex in vesicle trafficking. Here, TPC6A was determined to physically interact with tumor suppressor WWOX/FOR/WOX1. Transforming growth factor beta (TGF‐β) induces dissociation of the TPC6A/WWOX complex, which allows TPC6A to relocate to the nucleoli, followed by migrating out to the mitochondria. Cytosolic TPC6A is mainly a monomer, whereas its relocation to the mitochondria and nuclei allows presence of dimeric and multimeric forms, respectively, suggesting molecular alterations during trafficking. TPC6A aggregation is shown in the hippocampi, possessing increasing amounts of amyloid beta (Aβ), from postmortem patients with Alzheimer's disease (AD), compared to nondemented controls. In vitro experiments showed that TPC6A self‐polymerization may lead to Aβ superproduction and amyloid fibril formation. Also, downregulation of WWOX in the AD hippocampi facilitates TPC6A aggregation and Aβ superproduction in the brains. (supported by National Science Council and National Health Research Institute, Taiwan, Department of Defense, USA)