Self‐aggregating mutant TRAPPC6A from partial exon 1 gene deletion activates caspases, binds TIAF1, and generates amyloid beta in hippocampus

Abstract

TGF‐β‐induced factor TIAF1 forms aggregates in the hippocampus of normal individuals, and this may lead to the generation of amyloid beta (Aβ) and plaques as shown in Alzheimer's disease (AD). Here, we determined that TRAPPC6A gene deletion occurs at approximately a 3‐time higher incidence in AD than in normal controls. TRAPPC6A (TPC6A), a component of transport protein particle complex, forms aggregates with TIAF1 in the normal hippocampus, and the TIAF1/TPC6A complexes possess increasing amounts of Aβ in the AD hippocampus. TGF‐β induces aggregation of wild type TPC6A (TPC6Awt) and an N‐terminal deletion mutant (TPC6AΔ). Aggregated TPC6AΔ, but not TPC6Awt, upregulates p53 expression, causes caspase activation and Aβ superproduction in vitro. Tumor suppressor WWOX or WOX1 is frequently downregulated in AD. TPC6A physically interacts with WOX1, and TGF‐β1 dissociates the complex for causing TPC6A aggregation. Wwox−/− MEF cells were generated and prone to possess TPC6A and TIAF1 aggregates. Thus, downregulation of WOX1 is likely to elicit a sequential aggregation of TPC6A and TIAF1, respectively, for leading to the formation of Aβ and plaques in the brain. (Supported by NSC and NHRI, Taiwan, and DoD, USA)