TRAPPC6AΔ, TIAF1 and SH3GLB2 are initiators for amyloid beta plaque formation and tau aggregation in vivo

Abstract

Substantial evidence shows that tumor suppressor WW domain‐containing oxidoreductase, designated WWOX, FOR or WOX1, is involved in neurodegenerative diseases, neural disorders, cancer progression, and metabolic diseases. WWOX protects neurons from degeneration by binding tau and tau‐hyperphosphorylating enzymes GSK3β, ERK, and JNK1, and promotes neuronal differentiation. WWOX is frequently downregulated in the hippocampi of patients with Alzheimer's disease (AD). Indeed, WWOX may start to downregulate in the cortex and hippocampus in mid‐aged normal individuals. Both in vivo and in vitro evidence show that upon WWOX downregulation, a cascade of protein aggregation occurs, involving spontaneous relocation of TRAPPC6AΔ (trafficking protein particle complex 6A delta, TPC6AΔ) and TGFβ1‐induced anti‐apoptotic factor 1 (TIAF1) to the mitochondria. TPC6AΔ aggregates first and then TIAF1, followed by activating caspases and leading to amyloid precursor protein (APP) degradation and formation of amyloid beta (Aβ) plaques and tau tangles. Here we identified SH3GLB2 (SH3‐Domain GRB2‐Like Endophilin B2 ), whose aggregation is downstream that of TIAF1. The aggregates can be found in the AD hippocampi. A 31‐amino‐acid protein Zfra is highly effective in blocking and preventing the aggregation of TPC6AΔ, TIAF1, SH3GLB2, Aβ, and Tau. To characterize how the BAR domain‐containing SH3GLB2 aggregates, here we show that alteration of Tyr77 to Phe77 abolishes TGF‐β‐mediated polymerization, suggesting that Tyr77 phosphorylation is needed for SH3GLB2 aggregation. Activation of p53 by PRIMA‐1 abolishes SH3GLB2 aggregation, whereas inhibition of p53 activation by Pifithrin‐μ induces the aggregation. Induction of autophagy by thapsigargin accelerates SH3GLB2 aggregation. Transiently overexpressed SH3GLB2 causes apoptosis. Neurotoxin MPP+ induces neuronal death in vivo due in part to SH3GLB2 aggregation. Tumor suppressors p53 and WWOX are partners in cancer suppression. Loss of WWOX causes p53 instability. Conceivably, dysregulation of both p53 and WWOX results in initiation of the TPC6AΔ/TIAF1/SH3GLB2 aggregation cascade and leading to the formation of Aβ plaques and tau tangles of the neurodegeneration pathway.Support or Funding InformationMOST, Taiwan, and DoD, USA.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.