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- W2895981449 abstract "Neurons require intracellular transport of essential components for function and viability. Defects in axonal transport are implicated in many neurodegenerative disease, including Alzheimer's disease. Previously we found that reduction of PS stimulated the bi-directional axonal movement of APP vesicles, suggesting that PS can control motor function. Intriguingly, reduction of GSK3β also stimulated the bi-directional axonal motility of APP. While reduction of PS decreased GSK3β activity, excess active GSK3β increased motor binding to membranes. Therefore, we hypothesize that PS influences GSK3β activity during motor function perhaps via a mechanism that is similar to PS's role in the β-Catenin pathway. Using in vivo and biochemical analysis, we found that excess PS rescues GSK3β-mediated axonal transport defects. Intriguingly, functional PS and the catalytic region of PS (PS loop), which is known to bind to GSK3β was essential for this rescue. Disruption of PS function or deletion of the PSloop exacerbated GSK3β-mediated axonal transport defects via increasing motor protein binding to membranes. Further, active GSK3β associated with and phosphorylated kinesin-1 in vitro. Collectively, our observations propose a scaffolding mechanism for PS in which the loop region sequesters GSK3β away from motors for the proper regulation of motor function. We have identified a critical physiological role for the hydrophilic loop region of PS. These findings have important implications for our understanding of the complex functions of PS and for the complicated regulatory mechanisms that likely control motor protein activity during axonal transport in vivo." @default.
- W2895981449 created "2018-10-26" @default.
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- W2895981449 date "2018-07-01" @default.
- W2895981449 modified "2023-10-16" @default.
- W2895981449 title "P4‐261: THE LOOP REGION OF PRESENILIN (PS) REGULATES GSK‐3β‐MEDIATED EFFECTS ON MOTOR PROTEINS DURING AXONAL TRANSPORT" @default.
- W2895981449 doi "https://doi.org/10.1016/j.jalz.2018.07.083" @default.
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