FIGURE 4.

TPC6AΔ and TIAF1 in a cascade of protein aggregation and WWOX blocks the aggregation. (A) Representative human AD hippocampal tissue sections were pre-stained with Bielschowsky stain, followed by staining with specific antibody against TIAF1 (green), and Aβ (red) and DAPI for nuclei. A representative confocal image of a plaque is shown (Lee et al., 2010). (B) Shown is a TIAF1-containing plaque from a hippocampal section of a 9-month-old APP/PS1 transgenic mouse, containing Aβ aggregates in the center (Lee et al., 2010). (C) In representative human brain cortical tissue sections from AD patients and age-matched controls, a pS35-TPC6AΔ-containing plaque is shown. In negative controls, the immunizing peptide blocks the immunoreactivity (Chang et al., 2015). (D,E) Presence of pS35-TPC6AΔ and pT181-Tau aggregates is shown in the cortex and hippocampus of 3-week-old Wwox knockout mice (Chang et al., 2015). (F) Endogenous TPC6A and TPC6AΔ shuttle between nucleoli and mitochondria. Ser35 phosphorylation supports shuttling from the nucleus to the nucleolus, and Tyr112 phosphorylation is needed for translocation from the nucleolus to the mitochondrion (Chang and Chang, 2015). (G) Upon WWOX downregulation, a sequential protein aggregation cascade occurs. When WWOX level is reduced, pS35-TPC6AΔ starts to polymerize and recruit pS37-TIAF1 for further polymerization and accumulation in the outer membrane of mitochondria (Chang and Chang, 2015; Chang et al., 2015). The aggregated pS35-TPC6AΔ and pS37-TIAF1 cause caspase 3 activation and cytochrome c release. The activated caspase 3 leads to APP degradation and formation of Aβ and amyloid fibrils and Tau tangles. SH3GLB2 aggregation (Lee et al., 2017) occurs probably right after that of pS37-TIAF1. (All data are adapted with revisions in art work from Lee et al., 2010; Chang and Chang, 2015; Chang et al., 2015, under the guidelines of the publishers).