Fast axonal transport of the proteasome complex depends on membrane interaction and molecular motor function

CROMBERG L; OTERO MG; ALLOATTI M; POZO-DEVOTO V; ENCALADA S; ALMENAR-QUERALT A; FALZONE T; GOLDSTEIN L; BRUNO L

JOURNAL OF CELL SCIENCE

COMPANY OF BIOLOGISTS LTD

Lugar: Cambridge; Año: 2014 vol. 127 p. 1537 - 1549

0021-9533

Protein degradation by the ubiquitin-proteasome system in neurons depends on the correct delivery of the proteasome complex. In neurodegenerative diseases, protein aggregation and accumulation in axons link transport defects with degradation impairments; however, the transport properties of proteasomes remain unknown. Here, using in vivo experiments we revealed the fast anterograde transport of assembled and functional 26S proteasome complex. A high-resolution tracking system of fluorescent proteasomes exposed three motion regimes: actively driven proteasome axonal transport, diffusive behavior in a viscoelastic axonema and proteasome confined motion. We showed that active proteasome transport depends on motor function since reducing KIF5B motor subunit, resulted in impairments of the anterograde proteasome flux and the density of segmental velocities. Finally, we revealed that neuronal proteasomes interact with intracellular membranes and identify the coordinated transport of fluorescent proteasomes with synaptic precursor vesicles, Golgi-derived vesicles, lysosomes and mitochondria. All together, our results uncover the fast axonal transport as a new mechanism of proteasome delivery that depends on membrane cargo hitch-hiking and molecular motor function. We further hypothesize that defects in proteasome transport could trigger abnormal protein clearance in neurodegenerative diseases.