CONICET | Buscador de Institutos y Recursos Humanos

Local protein degradation through the ubiquitin-proteasome system (UPS) depends on the correct delivery of the proteasome complex. Axonal transport impairments and UPS defects are common features of neurodegenerative diseases. Axonal transport ensure that proteins synthesized at the soma are delivered throughout the axon to reach synapses. However, only few proteins are known to come back suggesting the need for a local degradation system far away from the soma. We focus our study on the axonal transport of the UPS. To reveal how proteasomes are transported along axons we performed sciatic nerves ligation staining against UPS subunits. Interestingly, proteasomes accumulate in the proximal region after ligation suggesting their movement throughout axons. To obtain specific dynamics, we performed live imaging movies from neurons transfected with a fluorescently fused proteasome subunit (α4-YFP). These movies revealed particles being transported in a fast and processive manner that correspond to motor-dependent proteasome movement. To identify if fast proteasome movement is associated with transported organelles we performed double color movies of neurons transfected with α4-YFP and stained for lysosomes or mitochondria. Surprisingly, proteasome associates to different organelles for its transport. To reveal if proteasome activity has an impact on axonal transport we recorded movies when proteasome is inhibited. This analysis showed a selective impairment in retrograde axonal transport of the proteasome without changing total particles densities. Thus, proteasomes are transported associated to membranes with fast anterograde and retrograde dynamics depending on molecular motors. Defects in UPS activity might selectively regulate the retrograde transport of the proteasome itself.