WWOX dysfunction induces sequential aggregation of TRAPPC6A?, TIAF1, tau and amyloid ?, and causes apoptosis.

ABSTRACT: Aggregated vesicle-trafficking protein isoform TRAPPC6A? (TPC6A?) has a critical role in causing caspase activation, tau aggregation and A? 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-?1 induces shuttling of endogenous wild-type TPC6A and TPC6A? in between nucleoli and mitochondria (~40-60?min per round trip), and WWOX reduces the shuttling time by 50%. TGF-?1 initially maximizes the binding of TPC6A? to the C-terminal tail of WWOX, followed by dissociation. TPC6A? then undergoes aggregation, together with TIAF1 (TGF-?1-induced antiapoptotic factor), in the mitochondria to induce apoptosis. An additional rescue scenario is that TGF-?1 induces Tyr33 phosphorylation and unfolding of WWOX and its the N-terminal WW domain slowly binds TPC6A? to block aggregation and apoptosis. Similarly, loss of WWOX induces TPC6A? polymerization first, then aggregation of TIAF1, amyloid ? and tau, and subsequent cell death, suggesting that a cascade of protein aggregation leads to neurodegeneration.

SUBMITTER: Chang JY 

PROVIDER: S-EPMC4981022 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature