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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.
Highlights
In a recent study, we reported the isolation of a truncated vesicletrafficking protein TRAPPC6AΔ (TPC6AΔ).[1]
When COS7 cells were transiently overexpressed with TPC6AΔ and treated with CCCP, CCCP rapidly induced loss of mitochondrial membrane permeability in less than 1 h, as (Figure 7f)
We have discovered for the first time that TGF-β1 induces two-way shuttling of TPC6A and TPC6AΔ in between nucleoli and mitochondria
Summary
We reported the isolation of a truncated vesicletrafficking protein TRAPPC6AΔ (TPC6AΔ).[1]. Unlike the wild-type protein, TPC6AΔ readily undergoes aggregation in the extracellular matrix.[1] TPC6AΔ aggregates or plaques have been found in the brain cortex and hippocampus in nondemented middle-aged humans and in patients with Alzheimer’s disease (AD), suggesting that TPC6AΔ is a marker for early onset of AD.[1] in 3-week-old Wwox gene knockout mice,[1] aggregates of TPC6AΔ, TIAF1 (TGF-β-induced antiapoptotic factor),[6,7] tau and amyloid beta (Aβ) can be found in the brain cortex. Important studies showed that homozygous nonsense mutations or other alterations of WWOX gene result in protein loss and cause patients to suffer from severe anomalies, including short stature and growth retardation, microcephaly with seizure, retinal degeneration and early death at 16 months of age.[13,23,24,25,26,27] We have determined that WWOX blocks neurodegeneration via binding tau and tauphosphorylating enzymes, including ERK, JNK and GSK-3β.8,28,29.
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