Molecular Mechanisms of Axonal Transport and Organelle Dynamics

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Molecular motors drive the active transport of organelles along the cellular cytoskeleton. Organelle transport is critically important in neurons, cells that extend axons reaching up to 1m in length. Axons have limited capacity for biosynthesis and degradation, thus axonal transport is required to supply newly synthesized proteins and organelles and to remove aging proteins and dysfunctional organelles. Accumulating evidence supports a cargo-specific model for axonal transport, in which the opposing activities of kinesin and cytoplasmic dynein motors are regulated by a distinct complement of regulatory proteins including scaffolding proteins and activating adaptors. We are interested in the mechanisms that regulate the transport of key organelles including mitochondria, autophagosomes, and synaptic vesicle precursors. We are also interested in the mechanisms that lead to site-specific delivery, such as the targeting of newly synthesized synaptic components to presynaptic sites along the axon. We hypothesize that this delivery is dependent on the localized regulation of cytoskeletal dynamics and organization, which directly affect the initiation and termination of cargo motility. Finally, we are interested in the mechanisms by which molecular motors and cytoskeletal dynamics actively remodel organelle membranes, leading to tubulation, fission and fusion. We tackle these questions using the synergistic approaches of live cell imaging and in vitro reconstitution with single molecule resolution. We will continue to focus on three major goals. Goal 1: Understanding the integrated regulation of organelle transport. Each type of organelle transported along the axon has a distinct pattern of motility that directly relates to its function. We seek to understand the specific mechanisms involved, focusing on essential axonal cargos, such as mitochondria and autophagosomes, testing the model that the cargo-specific, integrated regulation of motors allows for sustained transport over long time scales and distances. In Goal 2, we seek to understand the localized regulation of organelle dynamics within defined axonal zones, such as the delivery of synaptic vesicle precursors to presynaptic sites along the axon. These zones exhibit distinct patterns of cytoskeletal organization and cytoskeletal dynamics. We are interested in the mechanisms that enhance the rate-limiting step of transport initiation and control cargo delivery/retention at specific sites of cellular need. And in Goal 3, we will study organelle remodeling driven by molecular motors and/or cytoskeletal dynamics. Organelles such as mitochondria undergo dramatic remodeling via mechanisms including fission and fusion. We hypothesize that molecular motors and cytoskeletal filaments provide an adaptable toolbox that can be specifically tuned to regulate dynamic organelle morphology. Together, these approaches will provide important new insights into organelle dynamics in neurons. As deficits in axonal transport lead to neurodegeneration, we hope that our progress may provide new opportunities for targeted and effective therapeutic approaches.