Microtubule (MT) motors such as kinesin-1 and dynein play critical roles in the cell by orchestrating the movements of proteins, organelles and cytoskeletal elements. In neurons, kinesin transports cargo towards the synapse while dynein takes it back to the cell body. This bidirectional transport is possible because the motors interact with the MT cytoskeleton in different ways. Kinesin walks towards the plus-end of MTs, while dynein walks towards the minus-end. For a cargo bound to both types of motors, as is often the case, the direction of travel will be dictated by which type of motor is more active. For example, if kinesin is more active than dynein, the cargo will move towards the synapse. By locally controlling the relative activity of these two motors, the cell can steer cargo to its proper destination. However, it is not well understood this regulation of motor activity occurs. Just as the MT surface dictates which direction the motors travel, it may also play a role in modulating their activity. In axons, motors move along MTs decorated with a gradient of the MT-associated protein Tau. It has been proposed that Tau spatially controls MT traffic by differentially regulating motor activity. In this model, the presence of Tau promotes the relative activity of one type of motor over the other. Using single-molecule imaging, the motility of the two motors on MTs coated with different concentrations of Tau will be measured. Then, the mechanism by which Tau affects motors will be determined using a variety of synthetic obstacles and Tau mutants. Finally, the study will be extended to multi-motor cargo bound to both kinesin and dynein and determine how Tau affects bidirectional transport. Together, these experiments will reveal the role that Tau plays in regulating bidirectional cargo traffic.

Public Health Relevance

Bidirectional cargo transport in neurons is powered by microtubule motors and is critical for the health of the synapse. Tau is a microtubule-associated protein localized to the axon that has been implicated in both the etiology of Alzheimer's disease and the regulation of axonal transport. I will determine the mechanism by which Tau interacts with motor proteins and the role of Tau in regulating bidirectional transport.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM123655-03
Application #
9770903
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Brown, Anissa F
Project Start
2017-09-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Miscellaneous
Type
Organized Research Units
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704