CAREER: Regulation of retrograde transport initiation in the axon terminal

About This Grant

The cells that make up the brain called neurons contain internal structures that have to be positioned at precise locations within the cell. To ensure that these structures are transported to the right site, cells use molecular machines called motor proteins to move them to the right location. Such transport is essential for the formation and function of the nervous system. Defects in motor protein-based movement of specific structures in neurons have been linked to neurodegenerative and neurodevelopmental disorders. Despite the importance of this process, we still do not understand how these motor machines bind the right structures at the right time and how they “know” where to deliver them inside the cell. The proposed work will use in imaging, genetic manipulations, and biochemistry to determine how one of these motors, called dynein, is activated at the right time and place to bind specific structures to initiate their transport. A focus of this research is on the transport of the cellular structure called the autophagosome which is essential for the breakdown of cellular building blocks, as well as pathological aggregates in diseases such as Alzheimer’s, Huntington’s and Parkinson’s. Graduate and undergraduate students will participate in the proposed research and will be mentored by post-graduate trainees. This research will define fundamental aspects of dynein function, and form the foundation for future studies to target dynein within a therapeutic context. Dynein-dependent cargo transport is essential to move organelles, proteins, cytoskeletal elements, and signaling molecules from the axon terminal to the cell body in neurons. This process is highly regulated. Dynein accumulates in the axon terminal in an autoinhibited conformation prior to activation, cargo engagement, and transport initiation. How dynein is conditionally activated and cargo transport initiated is unknown. Given the ubiquitous localization of the motor, its activators, cargos, and cargo adaptors, conditional mechanisms must exist to trigger dynein-mediated transport for discreet cargos. This project will use in vivo imaging, biochemistry, and genetics to define the mechanisms of dynein motor activation and cargo transport initiation in the axon terminal of neurons. The results of the proposed work will delineate regulatory mechanisms for these essential steps to trigger dynein-dependent cargo transport initiation in the axon terminal. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.