“Mechanisms of Fast Axonal Transport of Prion Protein Vesicles and Infectious Prions”
Sandra E. Encalada, Ph.D. – The Scripps Research Institute, Dept. of Molecular and Experimental Medicine, Dept of Cell Biology, La Jolla, CA
Movement and positioning of vesicles inside axons is accomplished by the regulated active transport of microtubule-based kinesin and dynein motor proteins, which move along microtubules in anterograde and retrograde directions, respectively. The normal mammalian prion protein (PrPC) is a GPI-anchored protein that follows the secretory pathway inside vesicles toward the cell surface by an unknown mechanism. Once at the cell surface, PrPC is thought to interact with a number of ligands, including infectious scrapie (PrPSc), if present. Thus, trafficking of PrPC to the plasma membrane via an intact transport system might be a relevant mechanism for initiation of neurodegenerative conditions. Using imaging, biochemical, and genetic approaches, we show differential transport of the prion protein along axons by a subset of Kinesin-1 subunits, and by cytoplasmic dynein. We show that anterograde and retrograde motors associate to PrPC vesicles regardless of directionality or speed of movement, suggesting that association of motors to vesicles does not directly determine this activity but that regulatory factors instead of structural changes to motor-vesicle associations dictate the transport mechanics of these vesicles in axons. Furthermore, we show evidence for the fast axonal transport of infectious prions, and how prion infection might lead to the poisoning of an intact transport system in axons.