Investigating the molecular mechanisms governing developmental axon growth has been a useful approach for identifying new strategies for boosting axon regeneration after injury, with the goal of treating debilitating conditions such as spinal cord injury and vision loss. The picture emerging is that various axonal organelles are important centers for organizing the molecular mechanisms and machinery required for growth cone development and axon extension, and these have recently been targeted to stimulate robust regeneration in the injured adult central nervous system (CNS). This review summarizes recent literature highlighting a central role for organelles such as recycling endosomes, the endoplasmic reticulum, mitochondria, lysosomes, autophagosomes and the proteasome in developmental axon growth, and describes how these organelles can be targeted to promote axon regeneration after injury to the adult CNS. This review also examines the connections between these organelles in developing and regenerating axons, and finally discusses the molecular mechanisms within the axon that are required for successful axon growth.

Cambridge Institute for Medical Research University of Cambridge Cambridge CB2 0XY UK

Centre for Reconstructive Neuroscience Institute of Experimental Medicine CAS 142 20 Prague Czech Republic

John van Geest Centre for Brain Repair Department of Clinical Neurosciences University of Cambridge Cambridge CB2 0PY UK

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Banker G. The development of neuronal polarity: A retrospective view. J. Neurosci. 2018;38:1867–1873. doi: 10.1523/JNEUROSCI.1372-16.2018. PubMed DOI PMC

Schelski M., Bradke F. Neuronal polarization: From spatiotemporal signaling to cytoskeletal dynamics. Mol. Cell. Neurosci. 2017;84:11–28. doi: 10.1016/j.mcn.2017.03.008. PubMed DOI

Dotti C.G., Sullivan C.A., Banker G.A. The establishment of polarity by hippocampal neurons in culture. J. Neurosci. 1988;8:1454–1468. doi: 10.1523/JNEUROSCI.08-04-01454.1988. PubMed DOI PMC

Esch T., Lemmon V., Banker G. Local presentation of substrate molecules directs axon specification by cultured hippocampal neurons. J. Neurosci. 1999;19:6417–6426. doi: 10.1523/JNEUROSCI.19-15-06417.1999. PubMed DOI PMC

O’Donnell M., Chance R.K., Bashaw G.J. Axon Growth and Guidance: Receptor Regulation and Signal Transduction. Annu. Rev. Neurosci. 2009;32:383–412. doi: 10.1146/annurev.neuro.051508.135614. PubMed DOI PMC

Pfenninger K.H. Plasma membrane expansion: A neuron’s Herculean task. Nat. Rev. Neurosci. 2009;10:251–261. doi: 10.1038/nrn2593. PubMed DOI

Shen K., Scheiffele P. Genetics and cell biology of building specific synaptic connectivity. Annu. Rev. Neurosci. 2010;33:473–507. doi: 10.1146/annurev.neuro.051508.135302. PubMed DOI PMC

Lu Y., Brommer B., Tian X., Krishnan A., Meer M., Wang C., Vera D.L., Zeng Q., Yu D., Bonkowski M.S., et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020;588:124–129. doi: 10.1038/s41586-020-2975-4. PubMed DOI PMC

Hilton B.J., Bradke F. Can injured adult CNS axons regenerate by recapitulating development? Development. 2017;144:3417–3429. doi: 10.1242/dev.148312. PubMed DOI

He Z., Jin Y. Intrinsic Control of Axon Regeneration. Neuron. 2016;90:437–451. doi: 10.1016/j.neuron.2016.04.022. PubMed DOI

Kiyoshi C., Tedeschi A. Axon growth and synaptic function: A balancing act for axonal regeneration and neuronal circuit formation in CNS trauma and disease. Dev. Neurobiol. 2020;80:277–301. doi: 10.1002/dneu.22780. PubMed DOI PMC

Petrova V., Eva R. The Virtuous Cycle of Axon Growth: Axonal Transport of Growth-Promoting Machinery as an Intrinsic Determinant of Axon Regeneration. Dev. Neurobiol. 2018;78:898–925. doi: 10.1002/dneu.22608. PubMed DOI

Schwab M.E., Strittmatter S.M. Nogo limits neural plasticity and recovery from injury. Curr. Opin. Neurobiol. 2014;27:53–60. doi: 10.1016/j.conb.2014.02.011. PubMed DOI PMC

Bradke F., Fawcett J.W., Spira M.E. Assembly of a new growth cone after axotomy: The precursor to axon regeneration. Nat. Rev. Neurosci. 2012;13:183–193. doi: 10.1038/nrn3176. PubMed DOI

Ziv N.E., Spira M.E. Localized and transient elevations of intracellular Ca2+ induce the dedifferentiation of axonal segments into growth cones. J. Neurosci. 1997;17:3568–3579. doi: 10.1523/JNEUROSCI.17-10-03568.1997. PubMed DOI PMC

Chandran V., Coppola G., Nawabi H., Omura T., Versano R., Huebner E.A., Zhang A., Costigan M., Yekkirala A., Barrett L., et al. A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program. Neuron. 2016;89:956–970. doi: 10.1016/j.neuron.2016.01.034. PubMed DOI PMC

Costigan M., Befort K., Karchewski L., Griffin R.S., D’Urso D., Allchorne A., Sitarski J., Mannion J.W., Pratt R.E., Woolf C.J. Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC Neurosci. 2002;3:16. doi: 10.1186/1471-2202-3-16. PubMed DOI PMC

Park K.K., Liu K., Hu Y., Smith P.D., Wang C., Cai B., Xu B., Connolly L., Kramvis I., Sahin M., et al. Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN/mTOR Pathway. Science. 2008;322:963–966. doi: 10.1126/science.1161566. PubMed DOI PMC

Liu K., Lu Y., Lee J.K., Samara R., Willenberg R., Sears-Kraxberger I., Tedeschi A., Park K.K., Jin D., Cai B., et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 2010;13:1075–1081. doi: 10.1038/nn.2603. PubMed DOI PMC

Nieuwenhuis B., Barber A.C., Evans R.S., Pearson C.S., Fuchs J., MacQueen A.R., Erp S., Haenzi B., Hulshof L.A., Osborne A., et al. PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS. EMBO Mol. Med. 2020;12:e11674. doi: 10.15252/emmm.201911674. PubMed DOI PMC

Sun F., Park K.K., Belin S., Wang D., Lu T., Chen G., Zhang K., Yeung C., Feng G., Yankner B.A., et al. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature. 2011;480:372–375. doi: 10.1038/nature10594. PubMed DOI PMC

Smith P.D., Sun F., Park K.K., Cai B., Wang C., Kuwako K., Martinez-Carrasco I., Connolly L., He Z. SOCS3 Deletion Promotes Optic Nerve Regeneration In Vivo. Neuron. 2009;64:617–623. doi: 10.1016/j.neuron.2009.11.021. PubMed DOI PMC

Dupraz S., Grassi D., Bernis M.E., Sosa L., Bisbal M., Gastaldi L., Jausoro I., Caceres A., Pfenninger K.H., Quiroga S. The TC10-Exo70 Complex Is Essential for Membrane Expansion and Axonal Specification in Developing Neurons. J. Neurosci. 2009;29:13292–13301. doi: 10.1523/JNEUROSCI.3907-09.2009. PubMed DOI PMC

Porter K.R., Blum J. A study in microtomy for electron microscopy. Anat. Rec. 1953;117:685–709. doi: 10.1002/ar.1091170403. PubMed DOI

Nixon-Abell J., Obara C.J., Weigel A.V., Li D., Legant W.R., Xu C.S., Pasolli H.A., Harvey K., Hess H.F., Betzig E., et al. Increased spatiotemporal resolution reveals highly dynamic dense tubular matrices in the peripheral ER. Science. 2016;354:aaf3928. doi: 10.1126/science.aaf3928. PubMed DOI PMC

King C., Sengupta P., Seo A.Y., Lippincott-Schwartz J. ER membranes exhibit phase behavior at sites of organelle contact. Proc. Natl. Acad. Sci. USA. 2020;117:7225–7235. doi: 10.1073/pnas.1910854117. PubMed DOI PMC

Tsukita S., Ishikawa H. Three-Dimensional Distributionof Smooth Endoplasmic Reticulum in Myelinated Axons. J. Electron Microsc. 1976;25:141–149. PubMed

Droz B., Rambourg A., Koenig H.L. The smooth endoplasmic reticulum: Structure and role in the renewal of axonal membrane and synaptic vesicles by fast axonal tranport. Brain Res. 1975;93:1–13. doi: 10.1016/0006-8993(75)90282-6. PubMed DOI

González C., Cánovas J., Fresno J., Couve E., Court F.A., Couve A. Axons provide the secretory machinery for trafficking of voltage-gated sodium channels in peripheral nerve. Proc. Natl. Acad. Sci. USA. 2016;113:1823–1828. doi: 10.1073/pnas.1514943113. PubMed DOI PMC

Cioni J.-M., Lin J.Q., Holtermann A.V., Koppers M., Jakobs M.A.H., Azizi A., Turner-Bridger B., Shigeoka T., Franze K., Harris W.A., et al. Late Endosomes Act as mRNA Translation Platforms and Sustain Mitochondria in Axons. Cell. 2019;176:56–72.e15. doi: 10.1016/j.cell.2018.11.030. PubMed DOI PMC

Wu Y., Whiteus C., Xu C.S., Hayworth K.J., Weinberg R.J., Hess H.F., De Camilli P. Contacts between the endoplasmic reticulum and other membranes in neurons. Proc. Natl. Acad. Sci. USA. 2017;114:E4859–E4867. doi: 10.1073/pnas.1701078114. PubMed DOI PMC

Öztürk Z., O’Kane C.J., Pérez-Moreno J.J. Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration. Front. Neurosci. 2020;14:48. doi: 10.3389/fnins.2020.00048. PubMed DOI PMC

Westrate L.M., Lee J.E., Prinz W.A., Voeltz G.K. Form follows function: The importance of endoplasmic reticulum shape. Annu. Rev. Biochem. 2015;84:791–811. doi: 10.1146/annurev-biochem-072711-163501. PubMed DOI

Zhang H., Hu J. Shaping the Endoplasmic Reticulum into a Social Network. Trends Cell Biol. 2016;26:934–943. doi: 10.1016/j.tcb.2016.06.002. PubMed DOI

Hübner C.A., Kurth I. Membrane-shaping disorders: A common pathway in axon degeneration. Brain. 2014;137:3109–3121. doi: 10.1093/brain/awu287. PubMed DOI

Blackstone C. Cellular Pathways of Hereditary Spastic Paraplegia. Annu. Rev. Neurosci. 2012;35:25–47. doi: 10.1146/annurev-neuro-062111-150400. PubMed DOI PMC

Blackstone C., O’Kane C.J., Reid E. Hereditary spastic paraplegias: Membrane traffic and the motor pathway. Nat. Rev. Neurosci. 2011;12:31–42. doi: 10.1038/nrn2946. PubMed DOI PMC

Yalçın B., Zhao L., Stofanko M., O’Sullivan N.C., Kang Z.H., Roost A., Thomas M.R., Zaessinger S., Blard O., Patto A.L., et al. Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins. Elife. 2017;6:e23882. doi: 10.7554/eLife.23882. PubMed DOI PMC

O’Sullivan N.C., Jahn T.R., Reid E., O’Kane C.J. Reticulon-like-1, the Drosophila orthologue of the Hereditary Spastic Paraplegia gene reticulon 2, is required for organization of endoplasmic reticulum and of distal motor axons. Hum. Mol. Genet. 2012;21:3356–3365. doi: 10.1093/hmg/dds167. PubMed DOI PMC

Oliva M.K., Pérez-Moreno J.J., O’Shaughnessy J., Wardill T.J., O’Kane C.J. Endoplasmic Reticulum Lumenal Indicators in Drosophila Reveal Effects of HSP-Related Mutations on Endoplasmic Reticulum Calcium Dynamics. Front. Neurosci. 2020;14:816. doi: 10.3389/fnins.2020.00816. PubMed DOI PMC

English A.R., Voeltz G.K. Endoplasmic reticulum structure and interconnections with other organelles. Cold Spring Harb. Perspect. Biol. 2013;5:1–16. doi: 10.1101/cshperspect.a013227. PubMed DOI PMC

Farías G.G., Fréal A., Tortosa E., Stucchi R., Pan X., Portegies S., Will L., Altelaar M., Hoogenraad C.C. Feedback-Driven Mechanisms between Microtubules and the Endoplasmic Reticulum Instruct Neuronal Polarity. Neuron. 2019;102:184–201.e8. doi: 10.1016/j.neuron.2019.01.030. PubMed DOI

Petrova V., Pearson C.S., Ching J., Tribble J.R., Solano A.G., Yang Y., Love F.M., Watt R.J., Osborne A., Reid E., et al. Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Nat. Commun. 2020;11:5614. doi: 10.1038/s41467-020-19436-y. PubMed DOI PMC

Park S.H., Zhu P.P., Parker R.L., Blackstone C. Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J. Clin. Investig. 2010;120:1097–1110. doi: 10.1172/JCI40979. PubMed DOI PMC

Lim Y., Cho I.T., Schoel L.J., Cho G., Golden J.A. Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum/mitochondria contacts. Ann. Neurol. 2015;78:679–696. doi: 10.1002/ana.24488. PubMed DOI PMC

Rao K., Stone M.C., Weiner A.T., Gheres K.W., Zhou C., Deitcher D.L., Levitan E.S., Rolls M.M. Spastin, atlastin, and ER relocalization are involved in axon but not dendrite regeneration. Mol. Biol. Cell. 2016;27:3245–3256. doi: 10.1091/mbc.E16-05-0287. PubMed DOI PMC

Shorey M., Stone M.C., Mandel J., Rolls M.M. Neurons survive simultaneous injury to axons and dendrites and regrow both types of processes in vivo. Dev. Biol. 2020;465:108–118. doi: 10.1016/j.ydbio.2020.07.006. PubMed DOI PMC

Zhu P.P., Soderblom C., Tao-Cheng J.H., Stadler J., Blackstone C. SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development. Hum. Mol. Genet. 2006;15:1343–1353. doi: 10.1093/hmg/ddl054. PubMed DOI

Nozumi M., Togano T., Takahashi-Niki K., Lu J., Honda A., Taoka M., Shinkawa T., Koga H., Takeuchi K., Isobe T., et al. Identification of functional marker proteins in the mammalian growth cone. Proc. Natl. Acad. Sci. USA. 2009;106:17211–17216. doi: 10.1073/pnas.0904092106. PubMed DOI PMC

Saita S., Shirane M., Natume T., Iemura S., Nakayama K.I. Promotion of Neurite Extension by Protrudin Requires Its Interaction with Vesicle-associated Membrane Protein-associated Protein. J. Biol. Chem. 2009;284:13766–13777. doi: 10.1074/jbc.M807938200. PubMed DOI PMC

De Vincentiis S., Falconieri A., Mainardi M., Cappello V., Scribano V., Bizzarri R., Storti B., Dente L., Costa M., Raffa V. Extremely Low Forces Induce Extreme Axon Growth. J. Neurosci. 2020;40:4997–5007. doi: 10.1523/JNEUROSCI.3075-19.2020. PubMed DOI PMC

Vance J.E. Newly made phosphatidylserine and phosphatidylethanolamine are preferentially translocated between rat liver mitochondria and endoplasmic reticulum. J. Biol. Chem. 1991;266:89–97. doi: 10.1016/S0021-9258(18)52406-6. PubMed DOI

Vance J.E., Pan D., Campenot R.B., Bussiere M., Vance D.E. Evidence that the Major Membrane Lipids, Except Cholesterol, Are Made in Axons of Cultured Rat Sympathetic Neurons. J. Neurochem. 2008;62:329–337. doi: 10.1046/j.1471-4159.1994.62010329.x. PubMed DOI

De Chaves E.P., Vance D.E., Campenot R.B., Vance J.E. Axonal synthesis of phosphatidylcholine is required for normal axonal growth in rat sympathetic neurons. J. Cell Biol. 1995;128:913–918. doi: 10.1083/jcb.128.5.913. PubMed DOI PMC

Luarte A., Cornejo V.H., Bertin F., Gallardo J., Couve A. The axonal endoplasmic reticulum: One organelle—many functions in development, maintenance, and plasticity. Dev. Neurobiol. 2018;78:181–208. doi: 10.1002/dneu.22560. PubMed DOI

Jacquemyn J., Cascalho A., Goodchild R.E. The ins and outs of endoplasmic reticulum-controlled lipid biosynthesis. EMBO Rep. 2017;18:1905–1921. doi: 10.15252/embr.201643426. PubMed DOI PMC

Rodríguez-Berdini L., Orlando Ferrero G., Bustos Plonka F., Mauricio Cardozo Gizzi A., Prucca C.G., Quiroga S., Leonor Caputto B., Orio O.A. The moonlighting protein c-Fos activates lipid synthesis in neurons, an activity that is critical for cellular differentiation and cortical development. J. Biol. Chem. 2020;295:8808–8818. doi: 10.1074/jbc.RA119.010129. PubMed DOI PMC

Bakan I., Laplante M. Connecting mTORC1 signaling to SREBP-1 activation. Curr. Opin. Lipidol. 2012;23:226–234. doi: 10.1097/MOL.0b013e328352dd03. PubMed DOI

Ricoult S.J.H., Yecies J.L., Ben-Sahra I., Manning B.D. Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene. 2016;35:1250–1260. doi: 10.1038/onc.2015.179. PubMed DOI PMC

Ricoult S.J.H., Manning B.D. The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep. 2013;14:242–251. doi: 10.1038/embor.2013.5. PubMed DOI PMC

Lev S. Nonvesicular lipid transfer from the endoplasmic reticulum. Cold Spring Harb. Perspect. Biol. 2012;4:a013300. doi: 10.1101/cshperspect.a013300. PubMed DOI PMC

Lev S. Non-vesicular lipid transport by lipid-transfer proteins and beyond. Nat. Rev. Mol. Cell Biol. 2010;11:739–750. doi: 10.1038/nrm2971. PubMed DOI

Wojnacki J., Galli T. Membrane traffic during axon development. Dev. Neurobiol. 2016;76:1185–1200. doi: 10.1002/dneu.22390. PubMed DOI

Kaplan M.R., Simoni R.D. Intracellular transport of phosphatidylcholine to the plasma membrane. J. Cell Biol. 1985;101:441–445. doi: 10.1083/jcb.101.2.441. PubMed DOI PMC

Petkovic M., Jemaiel A., Daste F., Specht C.G., Izeddin I., Vorkel D., Verbavatz J.-M., Darzacq X., Triller A., Pfenninger K.H., et al. The SNARE Sec22b has a non-fusogenic function in plasma membrane expansion. Nat. Cell Biol. 2014;16:434–444. doi: 10.1038/ncb2937. PubMed DOI

Gallo A., Vannier C., Galli T. Endoplasmic Reticulum–Plasma Membrane Associations:Structures and Functions. Annu. Rev. Cell Dev. Biol. 2016;32:279–301. doi: 10.1146/annurev-cellbio-111315-125024. PubMed DOI

Gallo A., Danglot L., Giordano F., Hewlett B., Binz T., Vannier C., Galli T. Role of the Sec22b-E-Syt complex in neurite growth and ramification. J. Cell Sci. 2020;133:jcs247148. doi: 10.1242/jcs.247148. PubMed DOI

Blackmore M., Letourneau P.C. Protein synthesis in distal axons is not required for axon growth in the embryonic spinal cord. Dev. Neurobiol. 2007;67:976–986. doi: 10.1002/dneu.20395. PubMed DOI

Twiss J.L., Fainzilber M. Ribosomes in axons-scrounging from the neighbors? Trends Cell Biol. 2009;19:236–243. doi: 10.1016/j.tcb.2009.02.007. PubMed DOI

Tuck E., Cavalli V. Roles of membrane trafficking in nerve repair and regeneration. Commun. Integr. Biol. 2010;3:209–214. doi: 10.4161/cib.3.3.11555. PubMed DOI PMC

Gumy L.F., Tan C.L., Fawcett J.W. The role of local protein synthesis and degradation in axon regeneration. Exp. Neurol. 2010;223:28–37. doi: 10.1016/j.expneurol.2009.06.004. PubMed DOI PMC

Willis D., Ka W.L., Zheng J.Q., Chang J.H., Smit A., Kelly T., Merianda T.T., Sylvester J., Van Minnen J., Twiss J.L. Differential transport and local translation of cytoskeletal, injury-response, and neurodegeneration protein mRNAs in axons. J. Neurosci. 2005;25:778–791. doi: 10.1523/JNEUROSCI.4235-04.2005. PubMed DOI PMC

Kalinski A.L., Sachdeva R., Gomes C., Lee S.J., Shah Z., Houle J.D., Twiss J.L. mRNAs and protein synthetic machinery localize into regenerating spinal cord axons when they are provided a substrate that supports growth. J. Neurosci. 2015;35:10357–10370. doi: 10.1523/JNEUROSCI.1249-15.2015. PubMed DOI PMC

Verma P., Chierzi S., Codd A.M., Campbell D.S., Meyer R.L., Holt C.E., Fawcett J.W. Axonal Protein Synthesis and Degradation Are Necessary for Efficient Growth Cone Regeneration. J. Neurosci. 2005;25:331–342. doi: 10.1523/JNEUROSCI.3073-04.2005. PubMed DOI PMC

Merianda T.T., Lin A.C., Lam J.S.Y., Vuppalanchi D., Willis D.E., Karin N., Holt C.E., Twiss J.L. A functional equivalent of endoplasmic reticulum and Golgi in axons for secretion of locally synthesized proteins. Mol. Cell. Neurosci. 2009;40:128–142. doi: 10.1016/j.mcn.2008.09.008. PubMed DOI PMC

Van Erp S., van Berkel A.A., Feenstra E.M., Sahoo P.K., Wagstaff L., Twiss J.L., Fawcett J.W., Eva R., Ffrench-Constant C. Age-related loss of axonal regeneration is reflected by the level of local translation. Exp. Neurol. 2021:113594. doi: 10.1016/j.expneurol.2020.113594. PubMed DOI PMC

Holt C.E., Martin K.C., Schuman E.M. Local translation in neurons: Visualization and function. Nat. Struct. Mol. Biol. 2019;26:557–566. doi: 10.1038/s41594-019-0263-5. PubMed DOI

Vuppalanchi D., Merianda T.T., Donnelly C., Pacheco A., Williams G., Yoo S., Ratan R.R., Willis D.E., Twiss J.L. Lysophosphatidic acid differentially regulates axonal mRNA translation through 5’UTR elements. Mol. Cell. Neurosci. 2012;50:136–146. doi: 10.1016/j.mcn.2012.04.001. PubMed DOI PMC

Ying Z., Misra V., Verge V.M.K. Sensing nerve injury at the axonal ER: Activated Luman/CREB3 serves as a novel axonally synthesized retrograde regeneration signal. Proc. Natl. Acad. Sci. USA. 2014;111:16142–16147. doi: 10.1073/pnas.1407462111. PubMed DOI PMC

Friedman J.R., Voeltz G.K. The ER in 3D: A multifunctional dynamic membrane network. Trends Cell Biol. 2011;21:709–717. doi: 10.1016/j.tcb.2011.07.004. PubMed DOI PMC

De Gregorio C., Delgado R., Ibacache A., Sierralta J., Couve A. Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function. J. Cell Sci. 2017;130:3507–3516. doi: 10.1242/jcs.201657. PubMed DOI

Liu Y., Vidensky S., Ruggiero A.M., Maier S., Sitte H.H., Rothstein J.D. Reticulon RTN2B regulates trafficking and function of neuronal glutamate transporter EAAC1. J. Biol. Chem. 2008;283:6561–6571. doi: 10.1074/jbc.M708096200. PubMed DOI PMC

Kamemura K., Chihara T. Multiple functions of the ER-resident VAP and its extracellular role in neural development and disease. J. Biochem. 2019;165:391–400. doi: 10.1093/jb/mvz011. PubMed DOI

Esk C., Lindenhofer D., Haendeler S., Wester R.A., Pflug F., Schroeder B., Bagley J.A., Elling U., Zuber J., von Haeseler A., et al. A human tissue screen identifies a regulator of ER secretion as a brain size determinant. Science. 2020;370:eabb5390. doi: 10.1126/science.abb5390. PubMed DOI

Cui-Wang T., Hanus C., Cui T., Helton T., Bourne J., Watson D., Harris K.M., Ehlers M.D. Local zones of endoplasmic reticulum complexity confine cargo in neuronal dendrites. Cell. 2012;148:309–321. doi: 10.1016/j.cell.2011.11.056. PubMed DOI PMC

Valenzuela J.I., Jaureguiberry-Bravo M., Salas D.A., Ramírez O.A., Cornejo V.H., Lu H.E., Blanpied T.A., Couve A. Transport along the dendritic endoplasmic reticulum mediates the trafficking of GABAB receptors. J. Cell Sci. 2014;127:3382–3395. doi: 10.1242/jcs.151092. PubMed DOI PMC

Bowen A.B., Bourke A.M., Hiester B.G., Hanus C., Kennedy M.J. Golgi-Independent secretory trafficking through recycling endosomes in neuronal dendrites and spines. Elife. 2017;6:e27362. doi: 10.7554/eLife.27362. PubMed DOI PMC

Tojima T., Akiyama H., Itofusa R., Li Y., Katayama H., Miyawaki A., Kamiguchi H. Attractive axon guidance involves asymmetric membrane transport and exocytosis in the growth cone. Nat. Neurosci. 2007;10:58–66. doi: 10.1038/nn1814. PubMed DOI

Tojima T., Hines J.H., Henley J.R., Kamiguchi H. Second messengers and membrane trafficking direct and organize growth cone steering. Nat. Rev. Neurosci. 2011;12:191–203. doi: 10.1038/nrn2996. PubMed DOI PMC

Wada F., Nakata A., Tatsu Y., Ooashi N., Fukuda T., Nabetani T., Kamiguchi H. Myosin Va and Endoplasmic Reticulum Calcium Channel Complex Regulates Membrane Export during Axon Guidance. CellReports. 2016;15:1329–1344. doi: 10.1016/j.celrep.2016.04.021. PubMed DOI

Pavez M., Thompson A.C., Arnott H.J., Mitchell C.B., D’Atri I., Don E.K., Chilton J.K., Scott E.K., Lin J.Y., Young K.M., et al. STIM1 is required for remodeling of the endoplasmic reticulum and microtubule cytoskeleton in steering growth cones. J. Neurosci. 2019;39:5095–5114. doi: 10.1523/JNEUROSCI.2496-18.2019. PubMed DOI PMC

Kang F., Zhou M., Huang X., Fan J., Wei L., Boulanger J., Liu Z., Salamero J., Liu Y., Chen L. E-syt1 Re-arranges STIM1 Clusters to Stabilize Ring-shaped ER-PM Contact Sites and Accelerate Ca 2+ Store Replenishment. Sci. Rep. 2019;9:1–11. PubMed PMC

Zaman M.F., Nenadic A., Radojičić A., Rosado A., Beh C.T. Sticking With It: ER-PM Membrane Contact Sites as a Coordinating Nexus for Regulating Lipids and Proteins at the Cell Cortex. Front. Cell Dev. Biol. 2020;8:675. doi: 10.3389/fcell.2020.00675. PubMed DOI PMC

Cho Y., Sloutsky R., Naegle K.M., Cavalli V. XInjury-Induced HDAC5 nuclear export is essential for axon regeneration. Cell. 2013;155:894. doi: 10.1016/j.cell.2013.10.004. PubMed DOI PMC

Ohtake Y., Matsuhisa K., Kaneko M., Kanemoto S., Asada R., Imaizumi K., Saito A. Axonal Activation of the Unfolded Protein Response Promotes Axonal Regeneration Following Peripheral Nerve Injury. Neuroscience. 2018;375:34–48. doi: 10.1016/j.neuroscience.2018.02.003. PubMed DOI

Oñate M., Catenaccio A., Martínez G., Armentano D., Parsons G., Kerr B., Hetz C., Court F.A. Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury. Sci. Rep. 2016;6:1–14. doi: 10.1038/srep21709. PubMed DOI PMC

Valenzuela V., Collyer E., Armentano D., Parsons G.B., Court F.A., Hetz C. Activation of the unfolded protein response enhances motor recovery after spinal cord injury. Cell Death Dis. 2012;3:272. doi: 10.1038/cddis.2012.8. PubMed DOI PMC

Hu Y., Park K.K., Yang L., Wei X., Yang Q., Cho K.S., Thielen P., Lee A.H., Cartoni R., Glimcher L.H., et al. Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells. Neuron. 2012;73:445–452. doi: 10.1016/j.neuron.2011.11.026. PubMed DOI PMC

Halliday M., Mallucci G.R. Review: Modulating the unfolded protein response to prevent neurodegeneration and enhance memory Modulating the unfolded protein response to prevent neurodegeneration and enhance memory. Neuropathol. Appl. Neurobiol. 2015;41:414–427. doi: 10.1111/nan.12211. PubMed DOI PMC

Hetz C., Mollereau B. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat. Rev. Neurosci. 2014;15:233–249. doi: 10.1038/nrn3689. PubMed DOI

De Juan-Sanz J., Holt G.T., Schreiter E.R., de Juan F., Kim D.S., Ryan T.A. Axonal Endoplasmic Reticulum Ca2+ Content Controls Release Probability in CNS Nerve Terminals. Neuron. 2017;93:867–881.e6. doi: 10.1016/j.neuron.2017.01.010. PubMed DOI PMC

Lindhout F.W., Cao Y., Kevenaar J.T., Bodzęta A., Stucchi R., Boumpoutsari M.M., Katrukha E.A., Altelaar M., MacGillavry H.D., Hoogenraad C.C. VAP-SCRN1 interaction regulates dynamic endoplasmic reticulum remodeling and presynaptic function. EMBO J. 2019;38:e101345. doi: 10.15252/embj.2018101345. PubMed DOI PMC

Kuijpers M., Kochlamazashvili G., Stumpf A., Puchkov D., Swaminathan A., Lucht M.T., Krause E., Maritzen T., Schmitz D., Haucke V. Neuronal Autophagy Regulates Presynaptic Neurotransmission by Controlling the Axonal Endoplasmic Reticulum. Neuron. 2020;109:299–313.e9. doi: 10.1016/j.neuron.2020.10.005. PubMed DOI PMC

Ferri K.F., Kroemer G. Organelle-specific initiation of cell death pathways. Nat. Cell Biol. 2001;3:E255–E263. doi: 10.1038/ncb1101-e255. PubMed DOI

Rizzuto R., Pozzan T. Microdomains of intracellular Ca2+: Molecular determinants and functional consequences. Physiol. Rev. 2006;86:369–408. doi: 10.1152/physrev.00004.2005. PubMed DOI

Bock F.J., Tait S.W.G. Mitochondria as multifaceted regulators of cell death. Nat. Rev. Mol. Cell Biol. 2020;21:85–100. doi: 10.1038/s41580-019-0173-8. PubMed DOI

Lewis T.L., Turi G.F., Kwon S.-K., Losonczy A., Polleux F. Progressive Decrease of Mitochondrial Motility during Maturation of Cortical Axons In Vitro and In Vivo. Curr. Biol. 2016;26:2602–2608. doi: 10.1016/j.cub.2016.07.064. PubMed DOI PMC

Smit-Rigter L., Rajendran R., Silva C.A., Spierenburg L., Groeneweg F., Ruimschotel E.M., van Versendaal D., van der Togt C., Eysel U.T., Alexander Heimel J., et al. Mitochondrial Dynamics in Visual Cortex Are Limited In Vivo and Not Affected by Axonal Structural Plasticity. Curr. Biol. 2016;26:2609–2616. doi: 10.1016/j.cub.2016.07.033. PubMed DOI

Mar F.M., Simões A.R., Leite S., Morgado M.M., Santos T.E., Rodrigo I.S., Teixeira C.A., Misgeld T., Sousa M.M. CNS axons globally increase axonal transport after peripheral conditioning. J. Neurosci. 2014;34:5965–5970. doi: 10.1523/JNEUROSCI.4680-13.2014. PubMed DOI PMC

Misgeld T., Kerschensteiner M., Bareyre F.M., Burgess R.W., Lichtman J.W. Imaging axonal transport of mitochondria in vivo. Nat. Methods. 2007;4:559–561. doi: 10.1038/nmeth1055. PubMed DOI

O’Donnell K.C., Vargas M.E., Sagasti A. Wlds and PGC-1α regulate mitochondrial transport and oxidation state after axonal injury. J. Neurosci. 2013;33:14778–14790. doi: 10.1523/JNEUROSCI.1331-13.2013. PubMed DOI PMC

Han S.M., Baig H.S., Hammarlund M. Mitochondria Localize to Injured Axons to Support Regeneration. Neuron. 2016;92:1308–1323. doi: 10.1016/j.neuron.2016.11.025. PubMed DOI PMC

Hirokawa N., Noda Y., Tanaka Y., Niwa S. Kinesin superfamily motor proteins and intracellular transport. Nat. Rev. Mol. Cell Biol. 2009;10:682–696. doi: 10.1038/nrm2774. PubMed DOI

Saxton W.M., Hollenbeck P.J. The axonal transport of mitochondria. J. Cell Sci. 2012;125:2095–2104. doi: 10.1242/jcs.053850. PubMed DOI PMC

Lin M.Y., Sheng Z.H. Regulation of mitochondrial transport in neurons. Exp. Cell Res. 2015;334:35–44. doi: 10.1016/j.yexcr.2015.01.004. PubMed DOI PMC

Schwarz T.L. Mitochondrial trafficking in neurons. Cold Spring Harb. Perspect. Biol. 2013;5:a011304. doi: 10.1101/cshperspect.a011304. PubMed DOI PMC

Chang D.T.W., Reynolds I.J. Differences in mitochondrial movement and morphology in young and mature primary cortical neurons in culture. Neuroscience. 2006;141:727–736. doi: 10.1016/j.neuroscience.2006.01.034. PubMed DOI

Zhou B., Yu P., Lin M.-Y., Sun T., Chen Y., Sheng Z.-H. Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. J. Cell Biol. 2016;214:103–119. doi: 10.1083/jcb.201605101. PubMed DOI PMC

Kang J.-S., Tian J.-H., Pan P.-Y., Zald P., Li C., Deng C., Sheng Z.-H. Docking of Axonal Mitochondria by Syntaphilin Controls Their Mobility and Affects Short-Term Facilitation. Cell. 2008;132:137–148. doi: 10.1016/j.cell.2007.11.024. PubMed DOI PMC

Sun T., Qiao H., Pan P.Y., Chen Y., Sheng Z.H. Motile axonal mitochondria contribute to the variability of presynaptic strength. Cell Rep. 2013;4:413–419. doi: 10.1016/j.celrep.2013.06.040. PubMed DOI PMC

Steketee M.B., Moysidis S.N., Weinstein J.E., Kreymerman A., Silva J.P., Iqbal S., Goldberg J.L. Mitochondrial dynamics regulate growth cone motility, guidance, and neurite growth rate in perinatal retinal ganglion cells in vitro. Investig. Ophthalmol. Vis. Sci. 2012;53:7402–7411. doi: 10.1167/iovs.12-10298. PubMed DOI PMC

Kreymerman A., Buickians D.N., Nahmou M.M., Tran T., Galvao J., Wang Y., Sun N., Bazik L., Huynh S.K., Cho I.J., et al. MTP18 is a Novel Regulator of Mitochondrial Fission in CNS Neuron Development, Axonal Growth, and Injury Responses. Sci. Rep. 2019;9:1–13. doi: 10.1038/s41598-019-46956-5. PubMed DOI PMC

Chen H., Detmer S.A., Ewald A.J., Griffin E.E., Fraser S.E., Chan D.C. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell Biol. 2003;160:189–200. doi: 10.1083/jcb.200211046. PubMed DOI PMC

Davies V.J., Hollins A.J., Piechota M.J., Yip W., Davies J.R., White K.E., Nicols P.P., Boulton M.E., Votruba M. Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Hum. Mol. Genet. 2007;16:1307–1318. doi: 10.1093/hmg/ddm079. PubMed DOI

Lewis T.L., Kwon S.K., Lee A., Shaw R., Polleux F. MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size. Nat. Commun. 2018;9:1–15. doi: 10.1038/s41467-018-07416-2. PubMed DOI PMC

Kiryu-Seo S., Tamada H., Kato Y., Yasuda K., Ishihara N., Nomura M., Mihara K., Kiyama H. Mitochondrial fission is an acute and adaptive response in injured motor neurons. Sci. Rep. 2016;6:1–14. doi: 10.1038/srep28331. PubMed DOI PMC

Mattson M.P., Partin J. Evidence for mitochondrial control of neuronal polarity. J. Neurosci. Res. 1999;56:8–20. doi: 10.1002/(SICI)1097-4547(19990401)56:1<8::AID-JNR2>3.0.CO;2-G. PubMed DOI

Vaarmann A., Mandel M., Zeb A., Wareski P., Liiv J., Kuum M., Antsov E., Liiv M., Cagalinec M., Choubey V., et al. Mitochondrial biogenesis is required for axonal growth. Development. 2016;143:1981–1992. doi: 10.1242/dev.128926. PubMed DOI

Van Spronsen M., Mikhaylova M., Lipka J., Schlager M.A., van den Heuvel D.J., Kuijpers M., Wulf P.S., Keijzer N., Demmers J., Kapitein L.C., et al. TRAK/Milton Motor-Adaptor Proteins Steer Mitochondrial Trafficking to Axons and Dendrites. Neuron. 2013;77:485–502. doi: 10.1016/j.neuron.2012.11.027. PubMed DOI

Kalinski A.L., Kar A.N., Craver J., Tosolini A.P., Sleigh J.N., Lee S.J., Hawthorne A., Brito-Vargas P., Miller-Randolph S., Passino R., et al. Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition. J. Cell Biol. 2019;218:1871–1890. doi: 10.1083/jcb.201702187. PubMed DOI PMC

Cavallucci V., Bisicchia E., Cencioni M.T., Ferri A., Latini L., Nobili A., Biamonte F., Nazio F., Fanelli F., Moreno S., et al. Acute focal brain damage alters mitochondrial dynamics and autophagy in axotomized neurons. Cell Death Dis. 2014;5:e1545. doi: 10.1038/cddis.2014.511. PubMed DOI PMC

Sheng Z.H. The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring. Trends Cell Biol. 2017;27:403–416. doi: 10.1016/j.tcb.2017.01.005. PubMed DOI PMC

Cartoni R., Norsworthy M.W., Bei F., Wang C., Li S., Zhang Y., Gabel C.V., Schwarz T.L., He Z. The Mammalian-Specific Protein Armcx1 Regulates Mitochondrial Transport during Axon Regeneration. Neuron. 2016;92:1294–1307. doi: 10.1016/j.neuron.2016.10.060. PubMed DOI PMC

Han Q., Xie Y., Ordaz J.D., Huh A.J., Huang N., Wu W., Liu N., Chamberlain K.A., Sheng Z.H., Xu X.M. Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury. Cell Metab. 2020;31:623–641.e8. doi: 10.1016/j.cmet.2020.02.002. PubMed DOI PMC

Knowlton W.M., Hubert T., Wu Z., Chisholm A.D., Jin Y. A select subset of electron transport chain genes associated with optic atrophy link mitochondria to axon regeneration in Caenorhabditis elegans. Front. Neurosci. 2017;11:263. doi: 10.3389/fnins.2017.00263. PubMed DOI PMC

Rawson R.L., Yam L., Weimer R.M., Bend E.G., Hartwieg E., Horvitz H.R., Clark S.G., Jorgensen E.M. Axons degenerate in the absence of mitochondria in C. elegans. Curr. Biol. 2014;24:760–765. doi: 10.1016/j.cub.2014.02.025. PubMed DOI PMC

Tang N.H., Kim K.W., Xu S., Blazie S.M., Yee B.A., Yeo G.W., Jin Y., Chisholm A.D. The mRNA Decay Factor CAR-1/LSM14 Regulates Axon Regeneration via Mitochondrial Calcium Dynamics. Curr. Biol. 2020;30:865–876.e7. doi: 10.1016/j.cub.2019.12.061. PubMed DOI PMC

Chen Y., Sheng Z.H. Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport. J. Cell Biol. 2013;202:351–364. doi: 10.1083/jcb.201302040. PubMed DOI PMC

Wang X., Schwarz T.L. The Mechanism of Ca2+-Dependent Regulation of Kinesin-Mediated Mitochondrial Motility. Cell. 2009;136:163–174. doi: 10.1016/j.cell.2008.11.046. PubMed DOI PMC

Courchet J., Lewis T.L., Lee S., Courchet V., Liou D.Y., Aizawa S., Polleux F. Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell. 2013;153:1510. doi: 10.1016/j.cell.2013.05.021. PubMed DOI PMC

Tao K., Matsuki N., Koyama R. AMP-activated protein kinase mediates activity-dependent axon branching by recruiting mitochondria to axon. Dev. Neurobiol. 2014;74:557–573. doi: 10.1002/dneu.22149. PubMed DOI

Mehta S.T., Luo X., Park K.K., Bixby J.L., Lemmon V.P. Hyperactivated Stat3 boosts axon regeneration in the CNS. Exp. Neurol. 2016;280:115–120. doi: 10.1016/j.expneurol.2016.03.004. PubMed DOI PMC

Luo X., Ribeiro M., Bray E.R., Lee D.H., Yungher B.J., Mehta S.T., Thakor K.A., Diaz F., Lee J.K., Moraes C.T., et al. Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System. Cell Rep. 2016;15:398–410. doi: 10.1016/j.celrep.2016.03.029. PubMed DOI PMC

Fang Y., Soares L., Teng X., Geary M., Bonini N.M. A novel Drosophila model of nerve injury reveals an essential role of Nmnat in maintaining axonal integrity. Curr. Biol. 2012;22:590–595. doi: 10.1016/j.cub.2012.01.065. PubMed DOI PMC

Perry V.H., Brown M.C., Lunn E.R., Tree P., Gordon S. Evidence that Very Slow Wallerian Degeneration in C57BL/Ola Mice is an Intrinsic Property of the Peripheral Nerve. Eur. J. Neurosci. 1990;2:802–808. doi: 10.1111/j.1460-9568.1990.tb00472.x. PubMed DOI

Avery M.A., Rooney T.M., Pandya J.D., Wishart T.M., Gillingwater T.H., Geddes J.W., Sullivan P.G., Freeman M.R. Wld S prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca 2+ buffering. Curr. Biol. 2012;22:596–600. doi: 10.1016/j.cub.2012.02.043. PubMed DOI PMC

Yap C.C., Winckler B. Harnessing the Power of the Endosome to Regulate Neural Development. Neuron. 2012;74:440–451. doi: 10.1016/j.neuron.2012.04.015. PubMed DOI PMC

Hausott B., Klimaschewski L. Membrane turnover and receptor trafficking in regenerating axons. Eur. J. Neurosci. 2016;43:309–317. doi: 10.1111/ejn.13025. PubMed DOI

Tojima T., Kamiguchi H. Exocytic and endocytic membrane trafficking in axon development. Dev. Growth Differ. 2015;57:291–304. doi: 10.1111/dgd.12218. PubMed DOI

Villarroel-Campos D., Bronfman F.C., Gonzalez-Billault C. Rab GTPase signaling in neurite outgrowth and axon specification. Cytoskeleton. 2016;73:498–507. doi: 10.1002/cm.21303. PubMed DOI

Donaldson J.G., Johnson D.L., Dutta D. Rab and Arf G proteins in endosomal trafficking and cell surface homeostasis. Small GTPases. 2016;7:247–251. doi: 10.1080/21541248.2016.1212687. PubMed DOI PMC

Raiborg C., Stenmark H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature. 2009;458:445–452. doi: 10.1038/nature07961. PubMed DOI

Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 2009;10:513–525. doi: 10.1038/nrm2728. PubMed DOI

Welz T., Wellbourne-Wood J., Kerkhoff E. Orchestration of cell surface proteins by Rab11. Trends Cell Biol. 2014;24:407–415. doi: 10.1016/j.tcb.2014.02.004. PubMed DOI

Van Bergeijk P., Adrian M., Hoogenraad C.C., Kapitein L.C. Optogenetic control of organelle transport and positioning. Nature. 2015;518:111–114. doi: 10.1038/nature14128. PubMed DOI PMC

Eva R., Dassie E., Caswell P.T., Dick G., ffrench-Constant C., Norman J.C., Fawcett J.W. Rab11 and Its Effector Rab Coupling Protein Contribute to the Trafficking of 1 Integrins during Axon Growth in Adult Dorsal Root Ganglion Neurons and PC12 Cells. J. Neurosci. 2010;30:11654–11669. doi: 10.1523/JNEUROSCI.2425-10.2010. PubMed DOI PMC

Shirane M., Nakayama K.I. Protrudin Induces Neurite Formation by Directional Membrane Trafficking. Science. 2006;314:818–821. doi: 10.1126/science.1134027. PubMed DOI

Fujita A., Koinuma S., Yasuda S., Nagai H., Kamiguchi H., Wada N., Nakamura T. GTP hydrolysis of TC10 promotes neurite outgrowth through exocytic fusion of Rab11- and L1-containing vesicles by releasing exocyst component Exo70. PLoS ONE. 2013;8:e79689. doi: 10.1371/journal.pone.0079689. PubMed DOI PMC

Takano T., Urushibara T., Yoshioka N., Saito T., Fukuda M., Tomomura M., Hisanaga S.I. LMTK1 regulates dendritic formation by regulating movement of Rab11A-positive endosomes. Mol. Biol. Cell. 2014;25:1755–1768. doi: 10.1091/mbc.e14-01-0675. PubMed DOI PMC

Takano T., Tomomura M., Yoshioka N., Tsutsumi K., Terasawa Y., Saito T., Kawano H., Kamiguchi H., Fukuda M., Hisanaga S.I. LMTK1/AATYK1 is a novel regulator of axonal outgrowth that acts via Rab11 in a Cdk5-dependent manner. J. Neurosci. 2012;32:6587–6599. doi: 10.1523/JNEUROSCI.5317-11.2012. PubMed DOI PMC

Hisanaga S.I., Wei R., Huo A., Tomomura M. LMTK1, a Novel Modulator of Endosomal Trafficking in Neurons. Front. Mol. Neurosci. 2020;13 doi: 10.3389/fnmol.2020.00112. PubMed DOI PMC

Koseki H., Donegá M., Lam B.Y., Petrova V., van Erp S., Yeo G.S., Kwok J.C., ffrench-Constant C., Eva R., Fawcett J.W. Selective rab11 transport and the intrinsic regenerative ability of CNS axons. Elife. 2017;6:e26956. doi: 10.7554/eLife.26956. PubMed DOI PMC

Montagnac G., Sibarita J.B., Loubéry S., Daviet L., Romao M., Raposo G., Chavrier P. ARF6 Interacts with JIP4 to Control a Motor Switch Mechanism Regulating Endosome Traffic in Cytokinesis. Curr. Biol. 2009;19:184–195. doi: 10.1016/j.cub.2008.12.043. PubMed DOI

Eva R., Crisp S., Marland J.R.K., Norman J.C., Kanamarlapudi V., ffrench-Constant C., Fawcett J.W. ARF6 Directs Axon Transport and Traffic of Integrins and Regulates Axon Growth in Adult DRG Neurons. J. Neurosci. 2012;32:10352–10364. doi: 10.1523/JNEUROSCI.1409-12.2012. PubMed DOI PMC

Franssen E.H.P., Zhao R.-R., Koseki H., Kanamarlapudi V., Hoogenraad C.C., Eva R., Fawcett J.W. Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS. J. Neurosci. 2015;35:8359–8375. doi: 10.1523/JNEUROSCI.2850-14.2015. PubMed DOI PMC

Eva R., Koseki H., Kanamarlapudi V., Fawcett J.W. EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment. J. Cell Sci. 2017;130:3663–3675. doi: 10.1242/jcs.207423. PubMed DOI PMC

Quiroga S., Bisbal M., Cáceres A. Regulation of plasma membrane expansion during axon formation. Dev. Neurobiol. 2018;78:170–180. doi: 10.1002/dneu.22553. PubMed DOI

Winckler B., Yap C.C. Endocytosis and Endosomes at the Crossroads of Regulating Trafficking of Axon Outgrowth-Modifying Receptors. Traffic. 2011;12:1099–1108. doi: 10.1111/j.1600-0854.2011.01213.x. PubMed DOI PMC

Rozés-Salvador V., González-Billault C., Conde C. The Recycling Endosome in Nerve Cell Development: One Rab to Rule Them All? Front. Cell Dev. Biol. 2020;8:1479. doi: 10.3389/fcell.2020.603794. PubMed DOI PMC

Falk J., Konopacki F.A., Zivraj K.H., Holt C.E. Rab5 and rab4 regulate axon elongation in the Xenopus visual system. J. Neurosci. 2014;34:373–391. doi: 10.1523/JNEUROSCI.0876-13.2014. PubMed DOI PMC

Ponomareva O.Y., Eliceiri K.W., Halloran M.C. Charcot-Marie-Tooth 2b associated Rab7 mutations cause axon growth and guidance defects during vertebrate sensory neuron development. Neural Dev. 2016;11:2. doi: 10.1186/s13064-016-0058-x. PubMed DOI PMC

Nakazawa H., Sada T., Toriyama M., Tago K., Sugiura T., Fukuda M., Inagaki N. Rab33a mediates anterograde vesicular transport for membrane exocytosis and axon outgrowth. J. Neurosci. 2012;32:12712–12725. doi: 10.1523/JNEUROSCI.0989-12.2012. PubMed DOI PMC

Villarroel-Campos D., Henríquez D.R., Bodaleo F.J., Oguchi M.E., Bronfman F.C., Fukuda M., Gonzalez-Billault C. Rab35 functions in axon elongation are regulated by P53-related protein kinase in a mechanism that involves Rab35 protein degradation and the microtubule-associated protein 1B. J. Neurosci. 2016;36:7298–7313. doi: 10.1523/JNEUROSCI.4064-15.2016. PubMed DOI PMC

Deng C.Y., Lei W.L., Xu X.H., Ju X.C., Liu Y., Luo Z.G. JIP1 mediates anterograde transport of Rab10 cargos during neuronal polarization. J. Neurosci. 2014;34:1710–1723. doi: 10.1523/JNEUROSCI.4496-13.2014. PubMed DOI PMC

Liu Y., Xu X.H., Chen Q., Wang T., Deng C.Y., Song B.L., Du J.L., Luo Z.G. Myosin Vb controls biogenesis of post-Golgi Rab10 carriers during axon development. Nat. Commun. 2013;4:2005. doi: 10.1038/ncomms3005. PubMed DOI

Xu X.H., Deng C.Y., Liu Y., He M., Peng J., Wang T., Yuan L., Zheng Z.S., Blackshear P.J., Luo Z.G. MARCKS regulates membrane targeting of Rab10 vesicles to promote axon development. Cell Res. 2014;24:576–594. doi: 10.1038/cr.2014.33. PubMed DOI PMC

Hervera A., De Virgiliis F., Palmisano I., Zhou L., Tantardini E., Kong G., Hutson T., Danzi M.C., Perry R.B.T., Santos C.X.C., et al. Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. Nat. Cell Biol. 2018;20:307–319. doi: 10.1038/s41556-018-0039-x. PubMed DOI

Sekine Y., Lin-Moore A., Chenette D.M., Wang X., Jiang Z., Cafferty W.B., Hammarlund M., Strittmatter S.M. Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration. Cell Rep. 2018;23:415–428. doi: 10.1016/j.celrep.2018.03.058. PubMed DOI PMC

Xu H., Ren D. Lysosomal physiology. Annu. Rev. Physiol. 2015;77:57–80. doi: 10.1146/annurev-physiol-021014-071649. PubMed DOI PMC

Ferguson S.M. Axonal transport and maturation of lysosomes. Curr. Opin. Neurobiol. 2018;51:45–51. doi: 10.1016/j.conb.2018.02.020. PubMed DOI PMC

Inpanathan S., Botelho R.J. The lysosome signaling platform: Adapting with the Times. Front. Cell Dev. Biol. 2019;7:113. doi: 10.3389/fcell.2019.00113. PubMed DOI PMC

Ballabio A., Bonifacino J.S. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 2020;21:101–118. doi: 10.1038/s41580-019-0185-4. PubMed DOI

Farías G.G., Guardia C.M., De Pace R., Britt D.J., Bonifacino J.S. BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon. Proc. Natl. Acad. Sci. USA. 2017;114:E2955–E2964. doi: 10.1073/pnas.1616363114. PubMed DOI PMC

Kenific C.M., Wittmann T., Debnath J. Autophagy in adhesion and migration. J. Cell Sci. 2016;129:3685–3693. doi: 10.1242/jcs.188490. PubMed DOI PMC

Stavoe A.K.H., Holzbaur E.L.F. Autophagy in neurons. Annu. Rev. Cell Dev. Biol. 2019;35:477–500. doi: 10.1146/annurev-cellbio-100818-125242. PubMed DOI PMC

Maday S., Holzbaur E.L.F. Compartment-Specific Regulation of Autophagy in Primary Neurons. J. Neurosci. 2016;36:5933–5945. doi: 10.1523/JNEUROSCI.4401-15.2016. PubMed DOI PMC

Maday S., Wallace K.E., Holzbaur E.L.F. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. J. Cell Biol. 2012;196:407–417. doi: 10.1083/jcb.201106120. PubMed DOI PMC

Maday S., Holzbaur E.L.F. Article Autophagosome Biogenesis in Primary Neurons Follows an Ordered and Spatially Regulated Pathway. Dev. Cell. 2014;30:71–85. doi: 10.1016/j.devcel.2014.06.001. PubMed DOI PMC

Stavoe A.K.H., Hill S.E., Hall D.H., Colón-Ramos D.A. KIF1A/UNC-104 Transports ATG-9 to Regulate Neurodevelopment and Autophagy at Synapses. Dev. Cell. 2016;38:171–185. doi: 10.1016/j.devcel.2016.06.012. PubMed DOI PMC

Puri C., Vicinanza M., Ashkenazi A., Gratian M.J., Zhang Q., Bento C.F., Renna M., Menzies F.M., Rubinsztein D.C. The RAB11A-Positive Compartment Is a Primary Platform for Autophagosome Assembly Mediated by WIPI2 Recognition of PI3P-RAB11A. Dev. Cell. 2018;45:114–131.e8. doi: 10.1016/j.devcel.2018.03.008. PubMed DOI PMC

Shibata M., Lu T., Furuya T., Degterev A., Mizushima N., Yoshimori T., MacDonald M., Yankner B., Yuan J. Regulation of intracellular accumulation of mutant huntingtin by beclin 1. J. Biol. Chem. 2006;281:14474–14485. doi: 10.1074/jbc.M600364200. PubMed DOI

Simonsen A., Cumming R.C., Brech A., Isakson P., Schubert D.R., Finley K.D. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy. 2008;4:176–184. doi: 10.4161/auto.5269. PubMed DOI

Lipinski M.M., Zheng B., Lu T., Yan Z., Py B.F., Ng A., Xavier R.J., Li C., Yankner B.A., Scherzer C.R., et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA. 2010;107:14164–14169. doi: 10.1073/pnas.1009485107. PubMed DOI PMC

Chang J.T., Kumsta C., Hellman A.B., Adams L.M., Hansen M. Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging. Elife. 2017;6:e18459. doi: 10.7554/eLife.18459. PubMed DOI PMC

Glatigny M., Moriceau S., Rivagorda M., Ramos-Brossier M., Nascimbeni A.C., Lante F., Shanley M.R., Boudarene N., Rousseaud A., Friedman A.K., et al. Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline. Curr. Biol. 2019;29:435–448.e8. doi: 10.1016/j.cub.2018.12.021. PubMed DOI

Sakamoto K., Ozaki T., Ko Y.C., Tsai C.F., Gong Y., Morozumi M., Ishikawa Y., Uchimura K., Nadanaka S., Kitagawa H., et al. Glycan sulfation patterns define autophagy flux at axon tip via PTPRσ-cortactin axis. Nat. Chem. Biol. 2019;15:699–709. doi: 10.1038/s41589-019-0274-x. PubMed DOI

Tran A.P., Warren P.M., Silver J. Regulation of autophagy by inhibitory CSPG interactions with receptor PTPσ and its impact on plasticity and regeneration after spinal cord injury. Exp. Neurol. 2020;328:113276. doi: 10.1016/j.expneurol.2020.113276. PubMed DOI PMC

Galluzzi L., Green D.R. Autophagy-Independent Functions of the Autophagy Machinery. Cell. 2019;177:1682–1699. doi: 10.1016/j.cell.2019.05.026. PubMed DOI PMC

He M., Ding Y., Chu C., Tang J., Xiao Q., Luo Z.G. Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury. Proc. Natl. Acad. Sci. USA. 2016;113:11324–11329. doi: 10.1073/pnas.1611282113. PubMed DOI PMC

Kannan M., Bayam E., Wagner C., Rinaldi B., Kretz P.F., Tilly P., Roos M., McGillewie L., Bär S., Minocha S., et al. WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy. Proc. Natl. Acad. Sci. USA. 2017;114:E9308–E9317. doi: 10.1073/pnas.1713625114. PubMed DOI PMC

Wang B., Iyengar R., Li-Harms X., Joo J.H., Wright C., Lavado A., Horner L., Yang M., Guan J.L., Frase S., et al. The autophagy-inducing kinases, ULK1 and ULK2, regulate axon guidance in the developing mouse forebrain via a noncanonical pathway. Autophagy. 2018;14:796–811. doi: 10.1080/15548627.2017.1386820. PubMed DOI PMC

Nikoletopoulou V., Sidiropoulou K., Kallergi E., Dalezios Y., Tavernarakis N. Modulation of Autophagy by BDNF Underlies Synaptic Plasticity. Cell Metab. 2017;26:230–242.e5. doi: 10.1016/j.cmet.2017.06.005. PubMed DOI

Ban B.-K., Jun M.-H., Ryu H.-H., Jang D.-J., Ahmad S.T., Lee J.-A. Autophagy Negatively Regulates Early Axon Growth in Cortical Neurons. Mol. Cell. Biol. 2013;33:3907–3919. doi: 10.1128/MCB.00627-13. PubMed DOI PMC

Clarke J.-P., Mearow K. Autophagy inhibition in endogenous and nutrient-deprived conditions reduces dorsal root ganglia neuron survival and neurite growth in vitro. J. Neurosci. Res. 2016;94:653–670. doi: 10.1002/jnr.23733. PubMed DOI

Rabanal-Ruiz Y., Korolchuk V.I. mTORC1 and nutrient homeostasis: The central role of the lysosome. Int. J. Mol. Sci. 2018;19:818. doi: 10.3390/ijms19030818. PubMed DOI PMC

Wei X., Luo L., Chen J. Roles of mTOR Signaling in Tissue Regeneration. Cells. 2019;8:1075. doi: 10.3390/cells8091075. PubMed DOI PMC

Kim J., Guan K.L. mTOR as a central hub of nutrient signalling and cell growth. Nat. Cell Biol. 2019;21:63–71. doi: 10.1038/s41556-018-0205-1. PubMed DOI

Abe N., Borson S.H., Gambello M.J., Wang F., Cavalli V. Mammalian Target of Rapamycin (mTOR) activation increases axonal growth capacity of injured peripheral nerves. J. Biol. Chem. 2010;285:28034–28043. doi: 10.1074/jbc.M110.125336. PubMed DOI PMC

Danilov C.A., Steward O. Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice. Exp. Neurol. 2015;266:147–160. doi: 10.1016/j.expneurol.2015.02.012. PubMed DOI PMC

Geoffroy C.G., Hilton B.J., Tetzlaff W., Zheng B. Evidence for an Age-Dependent Decline in Axon Regeneration in the Adult Mammalian Central Nervous System. Cell Rep. 2016;15:238–246. doi: 10.1016/j.celrep.2016.03.028. PubMed DOI PMC

Leibinger M., Andreadaki A., Golla R., Levin E., Hilla A.M., Diekmann H., Fischer D. Boosting CNS axon regeneration by harnessing antagonistic effects of GSK3 activity. Proc. Natl. Acad. Sci. USA. 2017;114:E5454–E5463. doi: 10.1073/pnas.1621225114. PubMed DOI PMC

Leibinger M., Hilla A.M., Andreadaki A., Fischer D. GSK3-CRMP2 signaling mediates axonal regeneration induced by Pten knockout. Commun. Biol. 2019;2:318. doi: 10.1038/s42003-019-0524-1. PubMed DOI PMC

Miao L., Yang L., Huang H., Liang F., Ling C., Hu Y. MTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system. Elife. 2016;5:e14908. doi: 10.7554/eLife.14908. PubMed DOI PMC

Tassew N.G., Charish J., Shabanzadeh A.P., Luga V., Harada H., Farhani N., D’Onofrio P., Choi B., Ellabban A., Nickerson P.E.B., et al. Exosomes Mediate Mobilization of Autocrine Wnt10b to Promote Axonal Regeneration in the Injured CNS. Cell Rep. 2017;20:99–111. doi: 10.1016/j.celrep.2017.06.009. PubMed DOI

Pita-Thomas W., Mahar M., Joshi A., Gan D., Cavalli V. HDAC5 promotes optic nerve regeneration by activating the mTOR pathway. Exp. Neurol. 2019;317:271–283. doi: 10.1016/j.expneurol.2019.03.011. PubMed DOI PMC

Poulopoulos A., Murphy A.J., Ozkan A., Davis P., Hatch J., Kirchner R., Macklis J.D. Subcellular transcriptomes and proteomes of developing axon projections in the cerebral cortex. Nature. 2019;565:356–360. doi: 10.1038/s41586-018-0847-y. PubMed DOI PMC

Rodríguez A., Webster P., Ortego J., Andrews N.W. Lysosomes behave as Ca2+-regulated exocytic vesicles in fibroblasts and epithelial cells. J. Cell Biol. 1997;137:93–104. doi: 10.1083/jcb.137.1.93. PubMed DOI PMC

Reddy A., Caler E.V., Andrews N.W. Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Cell. 2001;106:157–169. doi: 10.1016/S0092-8674(01)00421-4. PubMed DOI

Jaiswal J.K., Andrews N.W., Simon S.M. Membrane proximal lysosomes are the major vesicles responsible for calcium-dependent exocytosis in nonsecretory cells. J. Cell Biol. 2002;159:625–635. doi: 10.1083/jcb.200208154. PubMed DOI PMC

Arantes R.M.E., Andrews N.W. A role for synaptotagmin VII-regulated exocytosis of lysosomes in neurite outgrowth from primary sympathetic neurons. J. Neurosci. 2006;26:4630–4637. doi: 10.1523/JNEUROSCI.0009-06.2006. PubMed DOI PMC

Czibener C., Sherer N.M., Becker S.M., Pypaert M., Hui E., Chapman E.R., Mothes W., Andrews N.W. Ca2+ and synaptotagmin VII-dependent delivery of lysosomal membrane to nascent phagosomes. J. Cell Biol. 2006;174:997–1007. doi: 10.1083/jcb.200605004. PubMed DOI PMC

Sato M., Yoshimura S., Hirai R., Goto A., Kunii M., Atik N., Sato T., Sato K., Harada R., Shimada J., et al. The role of VAMP7/TI-VAMP in cell polarity and lysosomal exocytosis in vivo. Traffic. 2011;12:1383–1393. doi: 10.1111/j.1600-0854.2011.01247.x. PubMed DOI

Naegeli K.M., Hastie E., Garde A., Wang Z., Keeley D.P., Gordon K.L., Pani A.M., Kelley L.C., Morrissey M.A., Chi Q., et al. Cell Invasion In Vivo via Rapid Exocytosis of a Transient Lysosome-Derived Membrane Domain. Dev. Cell. 2017;43:403–417.e10. doi: 10.1016/j.devcel.2017.10.024. PubMed DOI PMC

Jiang M., Meng J., Zeng F., Qing H., Hook G., Hook V., Wu Z., Ni J. Cathepsin B inhibition blocks neurite outgrowth in cultured neurons by regulating lysosomal trafficking and remodeling. J. Neurochem. 2020;155:300–312. doi: 10.1111/jnc.15032. PubMed DOI PMC

Jung J., Shin Y.H., Konishi H., Lee S.J., Kiyama H. Possible ATP release through lysosomal exocytosis from primary sensory neurons. Biochem. Biophys. Res. Commun. 2013;430:488–493. doi: 10.1016/j.bbrc.2012.12.009. PubMed DOI

Tam C., Idone V., Devlin C., Fernandes M.C., Flannery A., He X., Schuchman E., Tabas I., Andrews N.W. Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. J. Cell Biol. 2010;189:1027–1038. doi: 10.1083/jcb.201003053. PubMed DOI PMC

Castro-Gomes T., Corrotte M., Tam C., Andrews N.W. Plasma membrane repair is regulated extracellularly by proteases released from lysosomes. PLoS ONE. 2016;11:e0152583. PubMed PMC

Korhonen L., Lindholm D. The ubiquitin proteasome system in synaptic and axonal degeneration: A new twist to an old cycle. J. Cell Biol. 2004;165:27–30. doi: 10.1083/jcb.200311091. PubMed DOI PMC

Lee M., Liu Y.C., Chen C., Lu C.H., Lu S.T., Huang T.N., Hsu M.T., Hsueh Y.P., Cheng P.L. Ecm29-mediated proteasomal distribution modulates excitatory GABA responses in the developing brain. J. Cell Biol. 2020;219:e201903033. doi: 10.1083/jcb.201903033. PubMed DOI PMC

Minis A., Rodriguez J.A., Levin A., Liu K., Govek E.E., Hatten M.E., Steller H. The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance, and neuronal survival in mice. Proc. Natl. Acad. Sci. USA. 2019;116:24639–24650. doi: 10.1073/pnas.1911921116. PubMed DOI PMC

Otero M.G., Alloatti M., Cromberg L.E., Almenar-Queralt A., Encalada S.E., Pozo Devoto V.M., Bruno L., Goldstein L.S.B., Falzone T.L. Fast axonal transport of the proteasome complex depends on membrane interaction and molecular motor function. J. Cell Sci. 2014;127:1537–1549. doi: 10.1242/jcs.140780. PubMed DOI

Bingol B., Schuman E.M. Activity-dependent dynamics and sequestration of proteasomes in dendritic spines. Nature. 2006;441:1144–1148. doi: 10.1038/nature04769. PubMed DOI

Hamilton A.M., Zito K. Breaking it down: The ubiquitin proteasome system in neuronal morphogenesis. Neural Plast. 2013;2013:196848. doi: 10.1155/2013/196848. PubMed DOI PMC

DiAntonio A., Hicke L. Ubiquitin-Dependent Regulation of the Synapse. Annu. Rev. Neurosci. 2004;27:223–246. doi: 10.1146/annurev.neuro.27.070203.144317. PubMed DOI

Ohtani-Kaneko R., Takada K., Iigo M., Hara M., Yokosawa H., Kawashima S., Ohkawa K., Hirata K. Proteasome inhibitors which induce neurite outgrowth from PC12h cells cause different subcellular accumulations of multi-ubiquitin chains. Neurochem. Res. 1998;23:1435–1443. doi: 10.1023/A:1020763009488. PubMed DOI

Obin M., Mesco E., Gong X., Haas A.L., Joseph J., Taylor A. Neurite outgrowth in PC12 cells: Distinguishing the roles of ubiquitylation and ubiquitin-dependent proteolysis. J. Biol. Chem. 1999;274:11789–11795. doi: 10.1074/jbc.274.17.11789. PubMed DOI

Ōmura S., Fujimoto T., Otoguro K., Matsuzaki K., Moriguchi R., Tanaka H., Sasaki Y. Lactacystin, a novel microbial metabolite, induces neurito-genesis of neuroblastoma cells. J. Antibiot. 1991;44:113–116. doi: 10.7164/antibiotics.44.113. PubMed DOI

Klimaschewski L., Hausott B., Ingorokva S., Pfaller K. Constitutively expressed catalytic proteasomal subunits are up-regulated during neuronal differentiation and required for axon initiation, elongation and maintenance. J. Neurochem. 2006;96:1708–1717. doi: 10.1111/j.1471-4159.2006.03694.x. PubMed DOI

Laser H., Mack T.G.A., Wagner D., Coleman M.P. Proteasome inhibition arrests neurite outgrowth and causes dying-back degeneration in primary culture. J. Neurosci. Res. 2003;74:906–916. doi: 10.1002/jnr.10806. PubMed DOI

Zheng Q., Huang T., Zhang L., Zhou Y., Luo H., Xu H., Wang X. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Front. Aging Neurosci. 2016;8:303. doi: 10.3389/fnagi.2016.00303. PubMed DOI PMC

Njomen E., Tepe J.J. Proteasome Activation as a New Therapeutic Approach to Target Proteotoxic Disorders. J. Med. Chem. 2019;62:6469–6481. doi: 10.1021/acs.jmedchem.9b00101. PubMed DOI PMC

Tanaka K., Matsuda N. Proteostasis and neurodegeneration: The roles of proteasomal degradation and autophagy. Biochim. Biophys. Acta-Mol. Cell Res. 2014;1843:197–204. doi: 10.1016/j.bbamcr.2013.03.012. PubMed DOI

Jin E.J., Ko H.R., Hwang I., Kim B.S., Choi J.Y., Park K.W., Cho S.W., Ahn J.Y. Akt regulates neurite growth by phosphorylation-dependent inhibition of radixin proteasomal degradation. Sci. Rep. 2018;8:2557. doi: 10.1038/s41598-018-20755-w. PubMed DOI PMC

Tursun B., Schlüter A., Peters M.A., Viehweger B., Ostendorff H.P., Soosairajah J., Drung A., Bossenz M., Johnsen S.A., Schweizer M., et al. The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones. Genes Dev. 2005;19:2307–2319. doi: 10.1101/gad.1340605. PubMed DOI PMC

Yan D., Guo L., Wang Y. Requirement of dendritic Akt degradation by the ubiquitin-proteasome system for neuronal polarity. J. Cell Biol. 2006;174:415–424. doi: 10.1083/jcb.200511028. PubMed DOI PMC

Takabatake M., Goshima Y., Sasaki Y. Semaphorin-3A Promotes Degradation of Fragile X Mental Retardation Protein in Growth Cones via the Ubiquitin-Proteasome Pathway. Front. Neural Circuits. 2020;14:5. doi: 10.3389/fncir.2020.00005. PubMed DOI PMC

Campbell D.S., Holt C.E. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron. 2001;32:1013–1026. doi: 10.1016/S0896-6273(01)00551-7. PubMed DOI

Hsu M.-T., Guo C.-L., Liou A.Y., Chang T.-Y., Ng M.-C., Florea B.I., Overkleeft H.S., Wu Y.-L., Liao J.-C., Cheng P.-L. Stage-Dependent Axon Transport of Proteasomes Contributes to Axon Development. Dev. Cell. 2015;35:418–431. doi: 10.1016/j.devcel.2015.10.018. PubMed DOI

Knöferle J., Ramljak S., Koch J.C., Tönges L., Asif A.R., Michel U., Wouters F.S., Heermann S., Krieglstein K., Zerr I., et al. TGF-β 1 enhances neurite outgrowth via regulation of proteasome function and EFABP. Neurobiol. Dis. 2010;38:395–404. doi: 10.1016/j.nbd.2010.02.011. PubMed DOI

Park J.Y., Jang S.Y., Shin Y.K., Suh D.J., Park H.T. Calcium-dependent proteasome activation is required for axonal neurofilament degradation. Neural Regen. Res. 2013;8:3401. PubMed PMC

Staal J.A., Dickson T.C., Chung R.S., Vickers J.C. Disruption of the Ubiquitin Proteasome System following Axonal Stretch Injury Accelerates Progression to Secondary Axotomy. J. Neurotrauma. 2009;26:781–788. doi: 10.1089/neu.2008.0669. PubMed DOI

Valm A.M., Cohen S., Legant W.R., Melunis J., Hershberg U., Wait E., Cohen A.R., Davidson M.W., Betzig E., Lippincott-Schwartz J. Applying systems-level spectral imaging and analysis to reveal the organelle interactome. Nature. 2017;546:162–167. doi: 10.1038/nature22369. PubMed DOI PMC

Lee S., Wang W., Hwang J., Namgung U., Min K.T. Increased ER–mitochondria tethering promotes axon regeneration. Proc. Natl. Acad. Sci. USA. 2019;116:16074–16079. doi: 10.1073/pnas.1818830116. PubMed DOI PMC

Krauß M., Haucke V. A grab to move on: ER –endosome contacts in membrane protrusion formation and neurite outgrowth. EMBO J. 2015;34:1442–1444. doi: 10.15252/embj.201591553. PubMed DOI PMC

Wu H., Carvalho P., Voeltz G.K. Here, there, and everywhere: The importance of ER membrane contact sites. Science. 2018;361 doi: 10.1126/science.aan5835. PubMed DOI PMC

Mannan A.U., Krawen P., Sauter S.M., Boehm J., Chronowska A., Paulus W., Neesen J., Engel W. ZFYVE27 (SPG33), a Novel Spastin-Binding Protein, Is Mutated in Hereditary Spastic Paraplegia. Am. J. Hum. Genet. 2006;79:351–357. doi: 10.1086/504927. PubMed DOI PMC

Evans K., Keller C., Pavur K., Glasgow K., Conn B., Lauring B. Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance. Proc. Natl. Acad. Sci. USA. 2006;103:10666–10671. doi: 10.1073/pnas.0510863103. PubMed DOI PMC

Züchner S., Wang G., Tran-Viet K.N., Nance M.A., Gaskell P.C., Vance J.M., Ashley-Koch A.E., Pericak-Vance M.A. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am. J. Hum. Genet. 2006;79:365–369. doi: 10.1086/505361. PubMed DOI PMC

Beetz C., Schüle R., Deconinck T., Tran-Viet K.N., Zhu H., Kremer B.P.H., Frints S.G.M., Van Zelst-Stams W.A.G., Byrne P., Otto S., et al. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain. 2008;131:1078–1086. doi: 10.1093/brain/awn026. PubMed DOI PMC

Nishimura A.L., Mitne-Neto M., Silva H.C.A., Richieri-Costa A., Middleton S., Cascio D., Kok F., Oliveira J.R.M., Gillingwater T., Webb J., et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 2004;75:822–831. doi: 10.1086/425287. PubMed DOI PMC

Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., Yokochi M., Mizuno Y., Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–608. doi: 10.1038/33416. PubMed DOI

Valente E.M., Abou-Sleiman P.M., Caputo V., Muqit M.M.K., Harvey K., Gispert S., Ali Z., Del Turco D., Bentivoglio A.R., Healy D.G., et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304:1158–1160. doi: 10.1126/science.1096284. PubMed DOI

Valente E.M., Salvi S., Ialongo T., Marongiu R., Elia A.E., Caputo V., Romito L., Albanese A., Dallapiccola B., Bentivoglio A.R. PINK1 mutations are associated with sporadic early-onset Parkinsonism. Ann. Neurol. 2004;56:336–341. doi: 10.1002/ana.20256. PubMed DOI

Züchner S., Mersiyanova I.V., Muglia M., Bissar-Tadmouri N., Rochelle J., Dadali E.L., Zappia M., Nelis E., Patitucci A., Senderek J., et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat. Genet. 2004;36:449–451. doi: 10.1038/ng1341. PubMed DOI

Sidiropoulos P.N.M., Miehe M., Bock T., Tinelli E., Oertli C.I., Kuner R., Meijer D., Wollscheid B., Niemann A., Suter U. Dynamin 2 mutations in Charcot-Marie-Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination. Brain. 2012;135:1395–1411. doi: 10.1093/brain/aws061. PubMed DOI

Böhm J., Bulla M., Urquhart J.E., Malfatti E., Williams S.G., O’Sullivan J., Szlauer A., Koch C., Baranello G., Mora M., et al. ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy. Hum. Mutat. 2017;38:426–438. doi: 10.1002/humu.23172. PubMed DOI

Xu L., Wang X., Tong C. Endoplasmic Reticulum–Mitochondria Contact Sites and Neurodegeneration. Front. Cell Dev. Biol. 2020;8:428. doi: 10.3389/fcell.2020.00428. PubMed DOI PMC

Rieusset J. The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: An update. Cell Death Dis. 2018;9:388. doi: 10.1038/s41419-018-0416-1. PubMed DOI PMC

Rowland A.A., Voeltz G.K. Endoplasmic reticulum-mitochondria contacts: Function of the junction. Nat. Rev. Mol. Cell Biol. 2012;13:607–615. doi: 10.1038/nrm3440. PubMed DOI PMC

Marchi S., Patergnani S., Pinton P. The endoplasmic reticulum-mitochondria connection: One touch, multiple functions. Biochim. Biophys. Acta-Bioenerg. 2014;1837:461–469. doi: 10.1016/j.bbabio.2013.10.015. PubMed DOI

Bravo-Sagua R., Torrealba N., Paredes F., Morales P.E., Pennanen C., López-Crisosto C., Troncoso R., Criollo A., Chiong M., Hill J.A., et al. Organelle communication: Signaling crossroads between homeostasis and disease. Int. J. Biochem. Cell Biol. 2014;50:55–59. doi: 10.1016/j.biocel.2014.01.019. PubMed DOI

Grimm S. The ER-mitochondria interface: The social network of cell death. Biochim. Biophys. Acta-Mol. Cell Res. 2012;1823:327–334. doi: 10.1016/j.bbamcr.2011.11.018. PubMed DOI

Bernard-Marissal N., Médard J.J., Azzedine H., Chrast R. Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration. Brain. 2015;138:875–890. doi: 10.1093/brain/awv008. PubMed DOI

Bernard-Marissal N., Chrast R., Schneider B.L. Endoplasmic reticulum and mitochondria in diseases of motor and sensory neurons: A broken relationship? Cell Death Dis. 2018;9:1–16. doi: 10.1038/s41419-017-0125-1. PubMed DOI PMC

Stoica R., De Vos K.J., Paillusson S., Mueller S., Sancho R.M., Lau K.F., Vizcay-Barrena G., Lin W.L., Xu Y.F., Lewis J., et al. ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat. Commun. 2014;5:399. doi: 10.1038/ncomms4996. PubMed DOI PMC

Guardia-Laguarta C., Area-Gomez E., Rüb C., Liu Y., Magrané J., Becker D., Voos W., Schon E.A., Przedborski S. α-synuclein is localized to mitochondria-associated ER membranes. J. Neurosci. 2014;34:249–259. doi: 10.1523/JNEUROSCI.2507-13.2014. PubMed DOI PMC

Schon E.A., Area-Gomez E. Mitochondria-associated ER membranes in Alzheimer disease. Mol. Cell. Neurosci. 2013;55:26–36. doi: 10.1016/j.mcn.2012.07.011. PubMed DOI

Calì T., Ottolini D., Negro A., Brini M. α-synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions. J. Biol. Chem. 2012;287:17914–17929. doi: 10.1074/jbc.M111.302794. PubMed DOI PMC

Zampese E., Fasolato C., Kipanyula M.J., Bortolozzi M., Pozzan T., Pizzo P. Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk. Proc. Natl. Acad. Sci. USA. 2011;108:2777–2782. doi: 10.1073/pnas.1100735108. PubMed DOI PMC

Szabadkai G., Bianchi K., Várnai P., De Stefani D., Wieckowski M.R., Cavagna D., Nagy A.I., Balla T., Rizzuto R. Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J. Cell Biol. 2006;175:901–911. doi: 10.1083/jcb.200608073. PubMed DOI PMC

Trigo D., Goncalves M.B., Corcoran J.P.T. The regulation of mitochondrial dynamics in neurite outgrowth by retinoic acid receptor β signaling. FASEB J. 2019;33:7225–7235. doi: 10.1096/fj.201802097R. PubMed DOI PMC

Friedman J.R., DiBenedetto J.R., West M., Rowland A.A., Voeltz G.K. Endoplasmic reticulum-endosome contact increases as endosomes traffic and mature. Mol. Biol. Cell. 2013;24:1030–1040. doi: 10.1091/mbc.e12-10-0733. PubMed DOI PMC

Raiborg C., Wenzel E.M., Stenmark H. ER –endosome contact sites: Molecular compositions and functions. EMBO J. 2015;34:1848–1858. doi: 10.15252/embj.201591481. PubMed DOI PMC

Lu M., van Tartwijk F.W., Lin J.Q., Nijenhuis W., Parutto P., Fantham M., Christensen C.N., Avezov E., Holt C.E., Tunnacliffe A., et al. The structure and global distribution of the endoplasmic reticulum network are actively regulated by lysosomes. Sci. Adv. 2020;6:eabc7209. doi: 10.1126/sciadv.abc7209. PubMed DOI PMC

Raiborg C., Wenzel E.M., Pedersen N.M., Olsvik H., Schink K.O., Schultz S.W., Vietri M., Nisi V., Bucci C., Brech A., et al. Repeated ER–endosome contacts promote endosome translocation and neurite outgrowth. Nature. 2015;520:234–238. doi: 10.1038/nature14359. PubMed DOI

Allison R., Lumb J.H., Fassier C., Connell J.W., Martin D.T., Seaman M.N.J., Hazan J., Reid E. An ESCRT-spastin interaction promotes fission of recycling tubules from the endosome. J. Cell Biol. 2013;202:527–543. doi: 10.1083/jcb.201211045. PubMed DOI PMC

Allison R., Edgar J.R., Pearson G., Rizo T., Newton T., Günther S., Berner F., Hague J., Connell J.W., Winkler J., et al. Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia. J. Cell Biol. 2017;216:1337–1355. doi: 10.1083/jcb.201609033. PubMed DOI PMC

Eden E.R., White I.J., Tsapara A., Futter C.E. Membrane contacts between endosomes and ER provide sites for PTP1B-epidermal growth factor receptor interaction. Nat. Cell Biol. 2010;12:267–272. doi: 10.1038/ncb2026. PubMed DOI

Eden E.R., Sanchez-Heras E., Tsapara A., Sobota A., Levine T.P., Futter C.E. Annexin A1 Tethers Membrane Contact Sites that Mediate ER to Endosome Cholesterol Transport. Dev. Cell. 2016;37:473–483. doi: 10.1016/j.devcel.2016.05.005. PubMed DOI PMC

Kilpatrick B.S., Eden E.R., Hockey L.N., Yates E., Futter C.E., Patel S. An Endosomal NAADP-Sensitive Two-Pore Ca2+ Channel Regulates ER-Endosome Membrane Contact Sites to Control Growth Factor Signaling. Cell Rep. 2017;18:1636–1645. doi: 10.1016/j.celrep.2017.01.052. PubMed DOI PMC

Petkovic M., Oses-Prieto J., Burlingame A., Jan L.Y., Jan Y.N. TMEM16K is an interorganelle regulator of endosomal sorting. Nat. Commun. 2020;11:1–16. doi: 10.1038/s41467-020-17016-8. PubMed DOI PMC

Elbaz-Alon Y., Guo Y., Segev N., Harel M., Quinnell D.E., Geiger T., Avinoam O., Li D., Nunnari J. PDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria. Nat. Commun. 2020;11:1–14. doi: 10.1038/s41467-020-17451-7. PubMed DOI PMC

Hirabayashi Y., Kwon S.K., Paek H., Pernice W.M., Paul M.A., Lee J., Erfani P., Raczkowski A., Petrey D.S., Pon L.A., et al. ER-mitochondria tethering by PDZD8 regulates Ca2+ dynamics in mammalian neurons. Science. 2017;358:623–630. doi: 10.1126/science.aan6009. PubMed DOI PMC

Liao Y.C., Fernandopulle M.S., Wang G., Choi H., Hao L., Drerup C.M., Patel R., Qamar S., Nixon-Abell J., Shen Y., et al. RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether. Cell. 2019;179:147–164.e20. doi: 10.1016/j.cell.2019.08.050. PubMed DOI PMC

Lee J.E., Cathey P.I., Wu H., Parker R., Voeltz G.K. Endoplasmic reticulum contact sites regulate the dynamics of membraneless organelles. Science. 2020;367:eaay7108. doi: 10.1126/science.aay7108. PubMed DOI PMC

Cai Q., Zakaria H.M., Simone A., Sheng Z.H. Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons. Curr. Biol. 2012;22:545–552. doi: 10.1016/j.cub.2012.02.005. PubMed DOI PMC

Miller K.E., Sheetz M.P. Axonal mitochondrial transport and potential are correlated. J. Cell Sci. 2004;117:2791–2804. doi: 10.1242/jcs.01130. PubMed DOI

Lin M.Y., Cheng X.T., Tammineni P., Xie Y., Zhou B., Cai Q., Sheng Z.H. Releasing Syntaphilin Removes Stressed Mitochondria from Axons Independent of Mitophagy under Pathophysiological Conditions. Neuron. 2017;94:595–610.e6. doi: 10.1016/j.neuron.2017.04.004. PubMed DOI PMC

Zheng Y., Zhang X., Wu X., Jiang L., Ahsan A., Ma S., Xiao Z., Han F., Qin Z.H., Hu W., et al. Somatic autophagy of axonal mitochondria in ischemic neurons. J. Cell Biol. 2019;218:1891–1907. doi: 10.1083/jcb.201804101. PubMed DOI PMC

Wang X., Winter D., Ashrafi G., Schlehe J., Wong Y.L., Selkoe D., Rice S., Steen J., Lavoie M.J., Schwarz T.L. PINK1 and Parkin target miro for phosphorylation and degradation to arrest mitochondrial motility. Cell. 2011;147:893–906. doi: 10.1016/j.cell.2011.10.018. PubMed DOI PMC

Ashrafi G., Schlehe J.S., LaVoie M.J., Schwarz T.L. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J. Cell Biol. 2014;206:655–670. doi: 10.1083/jcb.201401070. PubMed DOI PMC

Gabriela Otero M., Fernandez Bessone I., Earle Hallberg A., Eneas Cromberg L., Cecilia De Rossi M., Saez T.M., Levi V., Almenar-Queralt A., Luis Falzone T. Proteasome Stress Leads to APP Axonal Transport Defects by Promoting Its Amyloidogenic Processing in Lysosomes. [(accessed on 6 March 2019)];2018 Available online: http://jcs.biologists.org/content/joces/early/2018/05/02/jcs.214536.full.pdf. PubMed

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