Slow axonal transport of cytosolic cargoes by dynamic-recruitment - a new traffic

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DESCRIPTION (provided by applicant): The vast majority of proteins in a neuron are synthesized in the cell bodies and transported along axons and up-to synapses by a process called axonal transport. Defects in slow axonal transport of proteins such as tau and ¿-synuclein have long been implicated in many neurodegenerative diseases including Alzheimer's and Parkinson's disease, however mechanisms of slow axonal transport of these (and other) cytosolic proteins is very poorly understood. We developed a model-system in cultured neurons to directly visualize the transport of cytosolic proteins (including ¿-synuclein) and found that these cargoes move coherently with a slow, motor-dependent anterograde bias. This type of movement has not been reported before and likely represents a new form of trafficking/transport within cells. Based on these and other in-vivo data from brains, we propose a new model where individual cytosolic protein monomers cluster and assemble into multi-protein complexes that are carried in neurons by molecular motors, a process we call 'dynamic clustering'. Here we propose a series of experiments to test predictions and hypotheses generated by this model. Upon completion, these studies would answer long-standing questions about the transport of these proteins and also open the door for investigation of their transport in pathologic states. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases like Alzheimer's and Parkinson's disease are a huge burden on our society and economy. These diseases are characterized by early deficits in synapses - the 'communication hub' of the brain; as well as impairments in axonal transport - the mechanism that that actually delivers various proteins into these synapses thereby maintaining their physiology throughout life. In pathologic states, the axonal transport of many proteins like tau and ¿-synuclein are thought to be impaired, and yet the mechanisms that move these proteins in axons and deliver them to the synapses is unknown. We have now developed new models where we can directly visualize and quantify the slow axonal transport of these pathology-related proteins in neurons and we hope that increased knowledge of the normal physiology will lead to advances in pathologic mechanisms that operate in these diseases. In the very least, these models will finally allow us to test specific disease- related hypotheses that has not been possible due to our inability to assay this transport modality.