title: WWOX dysfunction induces sequential aggregation of TRAPPC6AΔ, TIAF1, tau and amyloid β, and causes apoptosis.
abstract: Aggregated vesicle-trafficking protein isoform TRAPPC6AΔ (TPC6AΔ) has a critical role in causing caspase activation, tau aggregation and Aβ generation in the brains of nondemented middle-aged humans, patients with Alzheimer's disease (AD) and 3-week-old Wwox gene knockout mice. WWOX blocks neurodegeneration via interactions with tau and tau-phosphorylating enzymes. WWOX deficiency leads to epilepsy, mental retardation and early death. Here, we demonstrated that TGF-β1 induces shuttling of endogenous wild-type TPC6A and TPC6AΔ in between nucleoli and mitochondria (~40-60 min per round trip), and WWOX reduces the shuttling time by 50%. TGF-β1 initially maximizes the binding of TPC6AΔ to the C-terminal tail of WWOX, followed by dissociation. TPC6AΔ then undergoes aggregation, together with TIAF1 (TGF-β1-induced antiapoptotic factor), in the mitochondria to induce apoptosis. An additional rescue scenario is that TGF-β1 induces Tyr33 phosphorylation and unfolding of WWOX and its the N-terminal WW domain slowly binds TPC6AΔ to block aggregation and apoptosis. Similarly, loss of WWOX induces TPC6AΔ polymerization first, then aggregation of TIAF1, amyloid β and tau, and subsequent cell death, suggesting that a cascade of protein aggregation leads to neurodegeneration.
authors.affiliation: Institute of Molecular Medicine, National Cheng Kung University Medical College , Tainan, Taiwan.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan; Center for Infectious Disease and Signaling Research, National Cheng Kung University Medical College, Tainan, Taiwan; Advanced Optoelectronic Technology Center, National Cheng Kung University Medical College, Tainan, Taiwan; Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: N-S
authors.initials: NS
authors.lastname: Chang