Axonal Transport: Cargo-Specific Mechanisms of Motility and Regulation
2014; Cell Press; Volume: 84; Issue: 2 Linguagem: Inglês
10.1016/j.neuron.2014.10.019
ISSN1097-4199
AutoresSandra Maday, Alison E. Twelvetrees, Armen J. Moughamian, Erika L.F. Holzbaur,
Tópico(s)Ubiquitin and proteasome pathways
Resumo•Axonal transport of organelles and proteins is driven by kinesin and dynein motors•Cargo-bound motors are tightly regulated by Rabs, kinases, and scaffolding proteins•Defects in transport lead to neurodevelopmental or neurodegenerative disease Axonal transport is essential for neuronal function, and many neurodevelopmental and neurodegenerative diseases result from mutations in the axonal transport machinery. Anterograde transport supplies distal axons with newly synthesized proteins and lipids, including synaptic components required to maintain presynaptic activity. Retrograde transport is required to maintain homeostasis by removing aging proteins and organelles from the distal axon for degradation and recycling of components. Retrograde axonal transport also plays a major role in neurotrophic and injury response signaling. This review provides an overview of axonal transport pathways and discusses their role in neuronal function. Axonal transport is essential for neuronal function, and many neurodevelopmental and neurodegenerative diseases result from mutations in the axonal transport machinery. Anterograde transport supplies distal axons with newly synthesized proteins and lipids, including synaptic components required to maintain presynaptic activity. Retrograde transport is required to maintain homeostasis by removing aging proteins and organelles from the distal axon for degradation and recycling of components. Retrograde axonal transport also plays a major role in neurotrophic and injury response signaling. This review provides an overview of axonal transport pathways and discusses their role in neuronal function. The active transport of organelles, proteins, and RNA along the extended axons of neurons has long fascinated scientists. The remarkable fact that the axon depends on the biosynthetic and degradative activities of the soma, located up to a meter away, highlights the importance of active transport. Genetic evidence confirms an essential role for active transport in the neuron, as defects in many of the proteins involved are sufficient to cause either neurodevelopmental or neurodegenerative disease (Table 1).Table 1Neurodevelopmental and Neurodegenerative Diseases Caused by Mutations in the Axonal Transport MachineryProtein(s)Gene(s) with Known MutationDisease(s)ReferencesMotor ProteinsDyneinDYNC1H1CMT, SMA-LED, ID, MCD (Epilepsy)Weedon et al., 2011Weedon M.N. Hastings R. Caswell R. Xie W. Paszkiewicz K. Antoniadi T. Williams M. King C. Greenhalgh L. Newbury-Ecob R. Ellard S. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.Am. J. Hum. 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Open table in a new tab Abbreviations are as follows: AD, Alzheimer’s disease; ARID, autosomal recessive intellectual disability; CDCBM3, complex cortical dysplasia with other brain malformations-3; CFEOM, congenital fibrosis of the extraocular muscles; CMT, Charcot-Marie-Tooth disease; FTD, frontotemporal dementia; HD, Huntington’s disease; HMN, hereditary motor neuropathy; HSN, hereditary sensory neuropathy; HSP, hereditary spastic paraplegia; ID, intellectual disability; MCD, malformations of cortical development; MHAC, microhydranencephaly; MND, motor neuron disease; MR, mental retardation; SMA, spinal muscular atrophy; SMA-LED, SMA-lower extremity dominant; and SPAX, spastic ataxia. Metabolic cell-labeling experiments in the 1960s demonstrated the rapid movement of newly synthesized proteins along the axon in a process once termed “cellulifugal transport” (Weiss, 1967Weiss P. Neuronal dynamics and axonal flow. 3. Cellulifugal transport of labeled neuroplasm in isolated nerve preparations.Proc. Natl. Acad. Sci. USA. 1967; 57: 1239-1245Crossref PubMed Google Scholar). Experiments with drugs that disrupt the cellular cytoskeleton demonstrated that microtubules are required for active transport along the axon (Kreutzberg, 1969Kreutzberg G.W. Neuronal dynamics and axonal flow. IV. Blockage of intra-axonal enzyme transport by colchicine.Proc. Natl. Acad. Sci. USA. 1969; 62: 722-728Crossref PubMed Google Scholar). Pulse-chase labeling experiments led to the discovery of multiple phases of transport (reviewed in Griffin et al., 1976Griffin J.W. Price D.L. Drachman D.B. Engel W.K. Axonal transport to and from the motor nerve ending.Ann. N Y Acad. Sci. 1976; 274: 31-45Crossref PubMed Google Scholar). 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Kinesin associates with anterogradely transported membranous organelles in vivo.J. Cell Biol. 1991; 114: 295-302Crossref PubMed Google Scholar) and dynein as the motor for retrograde transport (Hirokawa et al., 1990Hirokawa N. Sato-Yoshitake R. Yoshida T. Kawashima T. Brain dynein (MAP1C) localizes on both anterogradely and retrogradely transported membranous organelles in vivo.J. Cell Biol. 1990; 111: 1027-1037Crossref PubMed Scopus (129) Google Scholar). Since these initial discoveries there has been considerable progress in understanding the mechanisms regulating the transport of organelles including mitochondria, lysosomes, autophagosomes, and endosomes (Figure 1), as well as the transport mechanisms involved in neurotrophic and injury signaling. Together, these studies support a model in which the regulation of transport is compartment specific. The complement of motors, adaptors, and scaffolding proteins bound to each cargo is organelle specific, leading to distinct patterns of motility and localization along the axon. Thus, while broad themes emerge, the specific mechanisms regulating the transport of each organelle or protein complex may be unique. Further, there is increasing evidence for the localized regulation of trafficking in key zones along the axon, such as the axon initial segment or in the distal axon. Here, we discuss both general themes and specific mechanisms involved in axonal transport. We will review recent progress and highlight some of the critical questions that remain, focusing on the mechanisms that regulate the dynamic trafficking of organelles along the axon. Microtubules, actin filaments, and intermediate filaments all contribute to the morphology and function of neurons, but axonal transport depends almost entirely on microtubules. Microtubules are polarized tubulin polymers with fast-growing plus ends and more stable minus ends, organized in a generally radial array in the soma with plus ends directed toward the cortex. In the axon, parallel microtubules form a unipolar array with plus ends oriented outward (Burton and Paige, 1981Burton P.R. Paige J.L. Polarity of axoplasmic microtubules in the olfactory nerve of the frog.Proc. Natl. Acad. Sci. USA. 1981; 78: 3269-3273Crossref PubMed Google Scholar, Stepanova et al., 2003Stepanova T. Slemmer J. Hoogenraad C.C. Lansbergen G. Dortland B. De Zeeuw C.I. Grosveld F. van Cappellen G. Akhmanova A. Galjart N. Visualization of microtubule growth in cultured neurons via the use of EB3-GFP (end-binding protein 3-green fluorescent protein).J. Neurosci. 2003; 23: 2655-2664Crossref PubMed Google Scholar), while in dendrites microtubule organization is more complex, with microtubules often organized in arrays with mixed polarity (Baas et al., 1988Baas P.W. Deitch J.S. 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Neurosci. 2011; 48: 349-358Crossref PubMed Scopus (33) Google Scholar). Microtubule-associated proteins, or MAPs, are bound along the length of axonal and dendritic microtubules. The canonical role for MAPs is to promote microtubule polymerization and stabilization; because of the high expression levels of MAPs in neurons, microtubules are generally more stable in these cells than in other cell types. MAPs may also function to regulate transport, as in vitro studies indicate they modulate the interaction of motors with the microtubule (Dixit et al., 2008bDixit R. Ross J.L. Goldman Y.E. Holzbaur E.L. Differential regulation of dynein and kinesin motor proteins by tau.Science. 2008; 319: 1086-1089Crossref PubMed Scopus (301) Google Scholar, Vershinin et al., 2007Vershinin M. Carter B.C. Razafsky D.S. King S.J. Gross S.P. Multiple-motor based transport and its regulation by Tau.Proc. Natl. Acad. Sci. USA. 2007; 104: 87-92Crossref PubMed Scopus (151) Google Scholar). The discovery of a specific class of MAPs, known as plus-end-interacting proteins or +TIPs, has shown that microtubules in axons can be dynamic. Live-cell imaging with GFP-labeled +TIPs that bind selectively to actively growing microtubule plus ends has shown that axonal microtubules exhibit the parameters of dynamic instability observed in nonneuronal cells, including slow growth and rapid shortening, punctuated by catastrophe and rescue events, respectively (Stepanova et al., 2003Stepanova T. Slemmer J. Hoogenraad C.C. Lansbergen G. Dortland B. De Zeeuw C.I. Grosveld F. van Cappellen G. Akhmanova A. Galjart N. Visualization of microtubule growth in cultured neurons via the use of EB3-GFP (end-binding protein 3-green fluorescent protein).J. Neurosci. 2003; 23: 2655-2664Crossref PubMed Google Scholar, Stepanova et al., 2010Stepanova T. Smal I. van Haren J. Akinci U. Liu Z. Miedema M. Limpens R. van Ham M. van der Reijden M. Poot R. et al.History-dependent catastrophes regulate axonal microtubule behavior.Curr. Biol. 2010; 20: 1023-1028Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). The +TIPS EB1 and EB3 recruit additional binding partners to microtubule ends, many of which have a role in the localized regulation of axonal transport (Moughamian et al., 2013Moughamian A.J. Osborn G.E. Lazarus J.E. Maday S. Holzbaur E.L. Ordered recruitment of dynactin to the microtubule plus-end is required for efficient initiation of retrograde axonal transport.J. Neurosci. 2013; 33: 13190-13203Crossref PubMed Scopus (6) Google Scholar). Direct posttranslational modification of tubulin is widespread in neurons (Janke and Bulinski, 2011Janke C. Bulinski J.C. Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions.Nat. Rev. Mol. Cell Biol. 2011; 12: 773-786Crossref PubMed Scopus (159) Google Scholar). Microtubule modifications directly modulate the activities of motor proteins (Sirajuddin et al., 2014Sirajuddin M. Rice L.M. Vale R.D. Regulation of microtubule motors by tubulin isotypes and post-translational modifications.Nat. Cell Biol. 2014; 16: 335-344Crossref PubMed Scopus (8) Google Scholar), potentially contributing to the polarized trafficking of motors into axons (Hammond et al., 2010Hammond J.W. Huang C.F. Kaech S. Jacobson C. Banker G. Verhey K.J. Posttranslational modifications of tubulin and the polarized transport of
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