Otero, M.G.; Alloatti, M.; Cromberg, L.E.; Almenar-Queralt, A.; Encalada, S.E.; Devoto, V.M.P.; Bruno, L.; Goldstein, L.S.B.; Falzone, T.L. "Fast axonal transport of the proteasome complex depends on membrane interaction and molecular motor function" (2014) Journal of Cell Science. 127(7):1537-1549
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Protein degradation by the ubiquitin-proteasome system in neurons depends on the correct delivery of the proteasome complex. In neurodegenerative diseases, aggregation and accumulation of proteins in axons link transport defects with degradation impairments; however, the transport properties of proteasomes remain unknown. Here, using in vivo experiments, we reveal the fast anterograde transport of assembled and functional 26S proteasome complexes. A high-resolution tracking system to follow fluorescent proteasomes revealed three types of motion: actively driven proteasome axonal transport, diffusive behavior in a viscoelastic axonema and proteasome-confined motion. We show that active proteasome transport depends on motor function because knockdown of the KIF5B motor subunit resulted in impairment of the anterograde proteasome flux and the density of segmental velocities. Finally, we reveal 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. Taken together, our results reveal fast axonal transport as a new mechanism of proteasome delivery that depends on membrane cargo 'hitch-hiking' and the function of molecular motors. We further hypothesize that defects in proteasome transport could promote abnormal protein clearance in neurodegenerative diseases. © 2014.Published by The Company of Biologists Ltd.


Documento: Artículo
Título:Fast axonal transport of the proteasome complex depends on membrane interaction and molecular motor function
Autor:Otero, M.G.; Alloatti, M.; Cromberg, L.E.; Almenar-Queralt, A.; Encalada, S.E.; Devoto, V.M.P.; Bruno, L.; Goldstein, L.S.B.; Falzone, T.L.
Filiación:Instituto de Biología Celular y Neurociencias (UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires CP 1121, Argentina
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, United States
Departamento de Física y IFIBA-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires CP 1428, Argentina
Department of Molecular and Experimental Medicine, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, United States
Palabras clave:Axonal transport; Kinesin-1; Membrane interaction; Molecular motors; Proteasome; Vesicles; molecular motor; proteasome; ubiquitin; proteasome; animal tissue; article; axoneme; clearance; controlled study; degenerative disease; diffusion; Golgi complex; in vivo study; intracellular membrane; lysosome; mitochondrion; molecular interaction; motor unit; mouse; nerve fiber transport; nonhuman; priority journal; protein degradation; synapse vesicle; viscoelasticity; animal; C57BL mouse; cell culture; cytology; hippocampus; intracellular membrane; metabolism; nerve fiber; nerve fiber transport; physiology; sciatic nerve; synaptosome; transport at the cellular level; Animals; Axonal Transport; Axons; Biological Transport; Cells, Cultured; Hippocampus; Intracellular Membranes; Mice; Mice, Inbred C57BL; Proteasome Endopeptidase Complex; Sciatic Nerve; Synaptic Vesicles; Synaptosomes
Página de inicio:1537
Página de fin:1549
Título revista:Journal of Cell Science
Título revista abreviado:J. Cell Sci.
CAS:proteasome, 140879-24-9; ubiquitin, 60267-61-0; Proteasome Endopeptidase Complex


  • Abe, N., Almenar-Queralt, A., Lillo, C., Shen, Z., Lozach, J., Briggs, S.P., Williams, D.S., Cavalli, V., Sunday driver interacts with two distinct classes of axonal organelles (2009) J. Biol. Chem., 284, pp. 34628-43463
  • Bence, N.F., Sampat, R.M., Kopito, R.R., Impairment of the ubiquitin-proteasome system by protein aggregation (2001) Science, 292, pp. 1552-2155
  • Bingol, B., Schuman, E.M., Activity-dependent dynamics and sequestration of proteasomes in dendritic spines (2006) Nature, 441, pp. 1144-2114
  • Bingol, B., Sheng, M., Deconstruction for reconstruction: the role of proteolysis in neural plasticity and disease (2011) Neuron, 69, pp. 22-23
  • Bingol, B., Wang, C.F., Arnott, D., Cheng, D., Peng, J., Sheng, M., Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines (2010) Cell, 140, pp. 567-657
  • Bohn, S., Beck, F., Sakata, E., Walzthoeni, T., Beck, M., Aebersold, R., Förster, F., Nickell, S., Structure of the 26S proteasome from Schizosaccharomyces pombe at subnanometer resolution (2010) Proc. Natl. Acad. Sci. USA, 107, pp. 20992-22099
  • Bossy-Wetzel, E., Schwarzenbacher, R., Lipton, S.A., Molecular pathways to neurodegeneration (2004) Nat. Med, 10 (SUPPL.), pp. S2-S9
  • Brangwynne, C.P., Koenderink, G.H., MacKintosh, F.C., Weitz, D.A., Intracellular transport by active diffusion (2009) Trends Cell Biol, 19, pp. 423-442
  • Bruno, L., Levi, V., Brunstein, M., Despósito, M.A., Transition to superdiffusive behavior in intracellular actin-based transport mediated by molecular motors (2009) Phys. Rev. E Stat. Nonlin. Soft Matter Phys., 80, p. 01191
  • Brunstein, M., Bruno, L., Desposito, M., Levi, V., Anomalous dynamics of melanosomes driven by myosin-V in Xenopus laevis melanophores (2009) Biophys. J., 97, pp. 1548-2155
  • Ciechanover, A., Brundin, P., The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg (2003) Neuron, 40, pp. 427-444
  • Djakovic, S.N., Schwarz, L.A., Barylko, B., DeMartino, G.N., Patrick, G.N., Regulation of the proteasome by neuronal activity and calcium/ calmodulin-dependent protein kinase II (2009) J. Biol. Chem., 284, pp. 26655-32666
  • Ehlers, M.D., Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system (2003) Nat. Neurosci., 6, pp. 231-324
  • Encalada, S.E., Szpankowski, L., Xia, C.H., Goldstein, L.S., Stable kinesin and dynein assemblies drive the axonal transport of mammalian prion protein vesicles (2011) Cell, 144, pp. 551-556
  • Falzone, T.L., Stokin, G.B., Imaging amyloid precursor protein in vivo: an axonal transport assay (2012) Methods Mol. Biol., 846, pp. 295-330
  • Falzone, T.L., Stokin, G.B., Lillo, C., Rodrigues, E.M., Westerman, E.L., Williams, D.S., Goldstein, L.S., Axonal stress kinase activation and tau misbehavior induced by kinesin-1 transport defects (2009) J. Neurosci., 29, pp. 5758-6576
  • Falzone, T.L., Gunawardena, S., McCleary, D., Reis, G.F., Goldstein, L.S., Kinesin-1 transport reductions enhance human tau hyperphosphorylation, aggregation and neurodegeneration in animal models of tauopathies (2010) Hum. Mol. Genet., 19, pp. 4399-4440
  • Goldstein, L.S., (2003) Do disorders of movement cause movement disorders and dementia? Neuron, 40, pp. 415-442
  • Gorbea, C., Pratt, G., Ustrell, V., Bell, R., Sahasrabudhe, S., Hughes, R.E., Rechsteiner, M., A protein interaction network for Ecm29 links the 26 S proteasome to molecular motors and endosomal components (2010) J. Biol. Chem., 285, pp. 31616-33163
  • Hirokawa, N., Niwa, S., Tanaka, Y., Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease (2010) Neuron, 68, pp. 610-663
  • Hoopfer, E.D., McLaughlin, T., Watts, R.J., Schuldiner, O., O'Leary, D.D., Luo, L., Wlds protection distinguishes axon degeneration following injury from naturally occurring developmental pruning (2006) Neuron, 50, pp. 883-889
  • Jin, S., Haggie, P.M., Verkman, A.S., Single-particle tracking of membrane protein diffusion in a potential: simulation, detection, and application to confined diffusion of CFTR Cl- channels (2007) Biophys. J., 93, pp. 1079-1108
  • Kalies, K.U., Allan, S., Sergeyenko, T., Kröger, H., Römisch, K., The protein translocation channel binds proteasomes to the endoplasmic reticulum membrane (2005) EMBO J, 24, pp. 2284-3229
  • Karki, S., Holzbaur, E.L., Cytoplasmic dynein and dynactin in cell division and intracellular transport (1999) Curr. Opin. Cell Biol., 11, pp. 45-55
  • Keck, S., Nitsch, R., Grune, T., Ullrich, O., Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimeŕs disease (2003) J. Neurochem., 85, pp. 115-212
  • Keller, J.N., Hanni, K.B., Markesbery, W.R., Impaired proteasome function in Alzheimer's disease (2000) J. Neurochem., 75, pp. 436-443
  • Lasek, R.J., Garner, J.A., Brady, S.T., Axonal transport of the cytoplasmic matrix (1984) J. Cell Biol., 99, pp. 212s-221s
  • Levi, V., Serpinskaya, A.S., Gratton, E., Gelfand, V., Organelle transport along microtubules in Xenopus melanophores: evidence for cooperation between multiple motors (2006) Biophys. J, 90, pp. 318-332
  • Luby-Phelps, K., Cytoarchitecture and physical properties of cytoplasm: volume, viscosity, diffusion, intracellular surface area (2000) Int. Rev. Cytol., 192, pp. 189-222
  • Mengual, E., Arizti, P., Rodrigo, J., Giménez-Amaya, J.M., Castaño, J.G., Immunohistochemical distribution and electron microscopic subcellular localization of the proteasome in the rat CNS (1996) J. Neurosci., 16, pp. 6331-6634
  • Murata, S., Yashiroda, H., Tanaka, K., Molecular mechanisms of proteasome assembly (2009) Nat. Rev. Mol. Cell Biol., 10, pp. 104-111
  • Nelson, S.R., Ali, M.Y., Trybus, K.M., Warshaw, D.M., Random walk of processive, quantum dot-labeled myosin Va molecules within the actin cortex of COS-7 cells (2009) Biophys. J., 97, pp. 509-551
  • Newman, R.H., Whitehead, P., Lally, J., Coffer, A., Freemont, P., 20S human proteasomes bind with a specific orientation to lipid monolayers in vitro (1996) Biochim. Biophys. Acta, 1281, pp. 111-211
  • Oddo, S., The ubiquitin-proteasome system in Alzheimer's disease (2008) J. Cell. Mol. Med., 12, pp. 363-437
  • Patrick, G.N., Synapse formation and plasticity: recent insights from the perspective of the ubiquitin proteasome system (2006) Curr. Opin. Neurobiol., 16, pp. 90-99
  • Popov, S., Poo, M.M., Diffusional transport of macromolecules in developing nerve processes (1992) J. Neurosci., 12, pp. 77-78
  • Rai, A.K., Rai, A., Ramaiya, A.J., Jha, R., Mallik, R., Molecular adaptations allow dynein to generate large collective forces inside cells (2013) Cell, 152, pp. 172-218
  • Reis, G.F., Yang, G., Szpankowski, L., Weaver, C., Shah, S.B., Robinson, J.T., Hays, T.S., Goldstein, L.S., Molecular motor function in axonal transport in vivo probed by genetic and computational analysis in Drosophila (2012) Mol. Biol. Cell, 23, pp. 1700-2171
  • Reits, E.A., Benham, A.M., Plougastel, B., Neefjes, J., Trowsdale, J., Dynamics of proteasome distribution in living cells (1997) EMBO J, 16, pp. 6087-6609
  • Robert, D., Aubertin, K., Bacri, J.C., Wilhelm, C., Magnetic nanomanipulations inside living cells compared with passive tracking of nanoprobes to get consensus for intracellular mechanics (2012) Phys. Rev. E Stat. Nonlin. Soft Matter Phys., 85, p. 01190
  • Rubinsztein, D.C., The roles of intracellular protein-degradation pathways in neurodegeneration (2006) Nature, 443, pp. 780-878
  • Saxton, M.J., Jacobson, K., Single-particle tracking: applications to membrane dynamics (1997) Annu. Rev. Biophys. Biomol. Struct., 26, pp. 373-439
  • Scott, D.A., Das, U., Tang, Y., Roy, S., Mechanistic logic underlying the axonal transport of cytosolic proteins (2011) Neuron, 70, pp. 441-445
  • Stokin, G.B., Goldstein, L.S., Axonal transport and Alzheimer's disease (2006) Annu. Rev. Biochem., 75, pp. 607-662
  • Stokin, G.B., Lillo, C., Falzone, T.L., Brusch, R.G., Rockenstein, E., Mount, S.L., Raman, R., Williams, D.S., Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease (2005) Science, 307, pp. 1282-2128
  • Tai, H.C., Schuman, E.M., Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction (2008) Nat. Rev. Neurosci., 9, pp. 826-883
  • Tai, H.C., Serrano-Pozo, A., Hashimoto, T., Frosch, M.P., Spires-Jones, T.L., Hyman, B.T., The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system (2012) Am. J. Pathol., 181, pp. 1426-2143
  • Tang, Y., Scott, D., Das, U., Gitler, D., Ganguly, A., Roy, S., Fast vesicle transport is required for the slow axonal transport of synapsin (2013) J. Neurosci., 33, pp. 15362-21537
  • Terada, S., Kinjo, M., Aihara, M., Takei, Y., Hirokawa, N., Kinesin-1/ Hsc70-dependent mechanism of slow axonal transport and its relation to fast axonal transport (2010) EMBO J, 29, pp. 843-885
  • Tseng, B.P., Green, K.N., Chan, J.L., Blurton-Jones, M., LaFerla, F.M., Abeta inhibits the proteasome and enhances amyloid and tau accumulation (2008) Neurobiol. Aging, 29, pp. 1607-2161
  • Upadhya, S.C., Ding, L., Smith, T.K., Hegde, A.N., Differential regulation of proteasome activity in the nucleus and the synaptic terminals (2006) Neurochem. Int., 48, pp. 296-330
  • Yi, J.J., Ehlers, M.D., Emerging roles for ubiquitin and protein degradation in neuronal function (2007) Pharmacol. Rev., 59, pp. 14-23
  • Zhao, Y., Hegde, A.N., Martin, K.C., The ubiquitin proteasome system functions as an inhibitory constraint on synaptic strengthening (2003) Curr. Biol., 13, pp. 887-889


---------- APA ----------
Otero, M.G., Alloatti, M., Cromberg, L.E., Almenar-Queralt, A., Encalada, S.E., Devoto, V.M.P., Bruno, L.,..., Falzone, T.L. (2014) . Fast axonal transport of the proteasome complex depends on membrane interaction and molecular motor function. Journal of Cell Science, 127(7), 1537-1549.
---------- CHICAGO ----------
Otero, M.G., Alloatti, M., Cromberg, L.E., Almenar-Queralt, A., Encalada, S.E., Devoto, V.M.P., et al. "Fast axonal transport of the proteasome complex depends on membrane interaction and molecular motor function" . Journal of Cell Science 127, no. 7 (2014) : 1537-1549.
---------- MLA ----------
Otero, M.G., Alloatti, M., Cromberg, L.E., Almenar-Queralt, A., Encalada, S.E., Devoto, V.M.P., et al. "Fast axonal transport of the proteasome complex depends on membrane interaction and molecular motor function" . Journal of Cell Science, vol. 127, no. 7, 2014, pp. 1537-1549.
---------- VANCOUVER ----------
Otero, M.G., Alloatti, M., Cromberg, L.E., Almenar-Queralt, A., Encalada, S.E., Devoto, V.M.P., et al. Fast axonal transport of the proteasome complex depends on membrane interaction and molecular motor function. J. Cell Sci. 2014;127(7):1537-1549.