Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain

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, TPC6A Delta, derived from alternative splicing of the TRAPPC6A (TPC6A) gene transcript. TPC6A Delta 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 TPC6A Delta occurs preceding A beta 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 TPC6A Delta in the cortex and hippocampus in 3-week-old mice, suggesting a role of WWOX in limiting TPC6A Delta aggregation. To support this hypothesis, in vitro analysis revealed that TGF-beta 1 induces dissociation of the ectopic complex of TPC6A Delta and WWOX in cells, and then TPC6A Delta undergoes Ser35 phosphorylation-dependent polymerization and induces caspase 3 activation and A beta production. Similarly, knockdown of WWOX by siRNA resulted in dramatic aggregation of TPC6A Delta. Together, when WWOX is downregulated, TPC6A Delta is phosphorylated at Ser35 and becomes aggregated for causing caspase activation that leads to Tau aggregation and A beta formation.