Measuring molecular motor forces to probe transport regulation in vivo




Leidel, Christina Paulette

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The cell relies on molecular motor proteins for long range transport of vesicles and organelles to maintain the organization required within the cell as it changes over time. Cargos move bidirectionally along microtubules due to the presence of multiple copies of opposite polarity motors. Individual motor properties have been teased out in vitro, but understanding how multiple motors cooperate in vivo has thus far been limited by many obstacles. The goal of this work is to study how multiple similar and dissimilar motors operate together in vivo. Since the function of motors is to generate force to haul cargos, I designed a novel optical trapping system capable of precisely measuring the forces exerted by molecular motors in their native environment, a living cell. Using this system, I find evidence that motors do not fight against each other, supporting the regulation model over the tug-of war model for bidirectional transport. I then study motor regulation in axons in the context of Alzheimer’s disease. I find that GSK-3, a kinase found in abnormal amounts in Alzheimer’s brains, is a negative regulator of transport. I show that GSK-3 regulates motor activity rather than cargo binding. Finally, I also use the optical trap to probe the viscosity of cytosol in vivo and investigate its implications on the cooperation of multiple motors.




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