Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-b-induced XXXX .

@entity18410 @entity10621 @entity584 @entity3446 @entity4012 @entity22030 @entity195 @entity528
UNASSIGNED: Amyloid-b (Ab)-induced @entity528 is considered central to the pathogenesis of @entity195 ( @entity195 ). Among several death modalities, autophagy and apoptosis play important roles in Ab-induced @entity528 suggesting that there may be regulatory mechanisms that initiate both cell death pathways. However, molecules that govern both pathways have not been identified. Here, we report that, upon Ab treatment, tribbles pseudokinase 3 ( @entity18410 , an ortholog of Drosophila Tribbles) is up-regulated in neurons both in vivo and in vitro Increased @entity18410 levels inhibited the activity of the kinase @entity584 by interacting with it. As a result, @entity4012 ( @entity4012 ), a transcription factor that is negatively regulated by @entity584 , was activated, translocated to the nucleus, and induced the pro-apoptotic gene @entity22030 (Bim). Conversely, @entity4012 responded to Ab insult by binding to the @entity18410 gene promoter, enhancing its expression. Our investigations further revealed that @entity18410 also induces autophagy. We found that @entity18410 indirectly activates @entity10621 ( @entity10621 ) by impeding phosphorylation of, and thus inactivating, a negative regulator of @entity10621 , mechanistic target of @entity3446 . @entity10621 activation augmented autophagosome formation and reduced autophagy flux. Thus, @entity18410 was required for formation of autophagosomes, which accumulated in neurons as autophagic flux was thwarted. Most importantly, silencing endogenous @entity18410 strongly protected neurons from Ab insult. Our results suggest that a self-amplifying feed-forward loop among @entity18410 , @entity584 , and @entity4012 in Ab-treated neurons induces both apoptosis and autophagy, culminating in @entity528 . Thus, @entity18410 may serve as a potential therapeutic target for @entity195 .
