Maintenance mechanisms of circuit-integrated axons
Vittoria Mariano1,2♯, Nuria Domínguez-Iturza1,2♯, Lukas J. Neukomm1* and Claudia Bagni1,3,*
1Department of Fundamental Neurosciences, University of Lausanne, Switzerland.
2Department of Neurosciences KU Leuven, VIB Center for Brain and Disease Research, Leuven, Belgium.
3Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy
♯Shared first authors:
*Shared last authors:
[email protected] [email protected]
Running title: Mechanisms for axon maintenance
Keywords: axonal homeostasis; axon degeneration; neuro-glia crosstalk; mitochondrial dysfunction
Abstract
Adult, circuit-integrated, neurons must be maintained and supported for the life span of their host. The attenuation of either maintenance or plasticity leads to impaired circuit function and ultimately to neurodegenerative disorders. Over the last few years, significant discoveries of molecular mechanisms were made that mediate the formation and maintenance of axons. Here, we highlight intrinsic and extrinsic mechanisms that ensure the health and survival of axons. We also briefly discuss examples of mutations associated with impaired axonal maintenance identified in specific neurological conditions. A better understanding of these mechanisms will therefore help to define targets for therapeutic interventions.
Highlights
• Following axonal growth and pathfinding, circuit integrated axons require local mechanisms for survival.
• Mitochondrial homeostasis, axoskeletal support, and glial nurturing are crucial for the maintenance of axons.
• Mechanisms of axonal support are impaired in neurodevelopmental and neurodegenerative diseases.
Introduction
To ensure sustained circuit function the nervous system has to establish proper wiring, integrate neuronal and non-neuronal cells, and at later stages battle the rigors of aging. Neurons use their axons for direct communication with other cells with almost no delay. Remarkably, the distance between a neuron and its target cell can be in the range of meters, e.g. in giraffes, blue whales, and humans [1,2]. While a meter doesn’t sound impressive, it is notable that a 1 m long axon is 20.000x longer than its 50 µm long soma, and it includes >99% of the neuronal volume (Figure 1). Furthermore, axons are highly complex, and they must remain plastic throughout life, which is essential for proper circuit performance. The maintenance of such large and elaborate structures is a major bioenergetic challenge for neurons, but it is essential since axons ensure continued circuit function.
How is an axon able to rapidly and locally cope with energetic and physical challenges to ensure its survival? Recently, an accumulating body of evidence supports the idea that an adult, circuit-integrated, axon cannot solely be supported by its own cell body (soma); the axon must utilize local axonal mechanisms that ensure its own autonomous survival. Besides soma- derived support mediated primarily by axonal transport, soma-independent mechanisms include: (1) intrinsic, local axonal maintenance; and (2) extrinsic glial functions to maintain axon homeostasis (Figure 2). Here, we provide an overview with some specific examples of soma- independent maintenance mechanisms that are essential for the life of the axon, and we also briefly discuss how attenuation of these mechanisms leads to neurological disorders.
Evidence of soma-independent axonal maintenance mechanisms
The soma of the neuron plays a key role in the life of the axon. A number of distinct cargos, such as RNAs, protein, vesicles and organelles, are synthesized and assembled in the soma and then transported via axonal transport out into the axon. Therefore, it is not surprising that axonal transport is crucial for the maintenance of this highly polarized structure, and defective or attenuated axonal transport culminates in axon degeneration (reviewed in [3]). There are other, distinct mechanisms that help to sustain complex axonal functions. For example, axons need to have the capability to respond quickly and locally to cues and challenges they are exposed to, without waiting for the cargo to be delivered from the soma. Such mechanisms could be of particular significance for long axons further away from their somas. There are several examples in the animal kingdom where the axon seems to be virtually autonomous and able to exist without its own soma. An unusual observation has been reported in the tiny wasp Megaphragma: during metamorphosis, neuronal somas are lysed, while axons are retained [4].
The long-term survival of anucleate axons can range from weeks to years, and this has been reported for many invertebrate phyla [5]. In Aplysia, after axonal injury (axotomy) the distal axon separated from the soma remains morphologically preserved for weeks rather than undergoing degeneration [6]. Similarly, in Drosophila mutants lacking an active axon self-destruction program, an axotomized axon remains for weeks morphologically preserved and capable of eliciting complex postsynaptic behaviors following optogenetic activation [7–9]. Taken together, these findings support the debated view of the “autonomous axon” [10].
How are axons able to ensure their own survival in the absence of soma-derived support for varying amounts of time? Below, we discuss recently discovered key mechanisms that help to explain these scenarios, and we conclude with examples of diseases in which axonopathies are due to defective mechanisms of axonal survival.
1) Local intrinsic survival mechanisms
1.1) Axonal mitochondria
Mitostasis, the maintenance of a healthy mitochondrial population (e.g. number, quality, movement and turnover), is essential for the life of a neuron (recently reviewed in [11]**).
Mitochondrial biogenesis is able to adapt in response to energy requirements of whole neurons, for example during development, and also more locally to oxidative stimuli, to electrical stimulation, or to hormones. Importantly, mitochondria are also crucial for axonal maintenance, as observed in C. elegans, where axons undergo degeneration when mitochondria are depleted [12].
Local axonal synthesis of proteins is an important mechanism for stabilizing mitochondria, and thereby the axon. In cultured embryonic Xenopus retinal neurons, Lamin B2 (LB2) is normally associated with nuclear membranes, however, when triggered by guidance cues, lb2 mRNA is also transported into axons where it is locally translated and incorporated into mitochondria [13]**. This is a remarkable example of axonal protein synthesis sustaining mitochondria and, therefore, axonal survival. In contrast, inhibition of axonal LB2 synthesis
results in axon degeneration. The anti-apoptotic protein Bclw is also locally translated in axons.
Its synthesis prevents the disruption of mitochondria, which in turn ensures axonal health in rat and mouse sensory neurons [14]. Thus, local axonal translation of proteins that strengthen mitochondrial performance, or inhibit their destruction, provides a key mechanism for axon survival.
Mobility of mitochondria in axons is another key feature of axonal survival. Axonal mitochondria exist in a specific elongated shape and are either anchored or mobile (70% and 30%, respectively) [15]. Anchored mitochondria serve as a local energy source to sustain high energy demands, for example ATP for motor proteins, axonal protein synthesis, axonal branching, and Ca2+ storage [16] (reviewed in [17]*). By contrast, mobile mitochondria are predominantly involved in the cycle of fusion/fission [18,19]. Mitochondrial mobility requires Miro and Milton, molecular adaptors that mediate the attachment of mitochondria to molecular motors [20,21]. Remarkably, in Drosophila, knock-down of Milton, which links mitochondria to kinesins, leads to axon degeneration [22]. This finding builds on a previous observation in a Drosophila model of Alzheimer’s disease (AD) [23]: neuronal expression of toxic amyloid-β peptides (a shortened, 42 amino acid peptide, Aβ42) results in an accumulation of mitochondria in the soma, while their number is reduced in axons. These flies show age-dependent behavioral phenotypes that are enhanced by attenuation of mitochondrial transport through knock-down of either Miro or Milton [24]. Therefore, not only the presence, but also the motility, of axonal mitochondria are important for axonal survival.
Mitochondrial quality control mechanisms also contribute to axonal survival. Mitochondria are morphologically highly plastic, which allows them to adapt to energy demand and supply. The main two features of adaptation are mitochondrial elongation (fusion) and fragmentation (fission): an environment rich in nutrients is associated with a fragmented mitochondrial network, while starvation tends to elongate mitochondria (reviewed in [25]). It is quite remarkable that mutations disrupting mitochondrial fusion (e.g. Mitofusin2) cause specific axonal degeneration in cultured sensory neurons [26]. However, mutations that affect mitochondrial fission (e.g. human dynamin-related protein 1( Drp1)) lead to loss of mitochondria in dopaminergic neuron axons [27] and also to deficient axonal bioenergetic function in the hippocampus [28]: in both cases ultimately resulting in axonal degeneration. These observations suggest that disrupting mitochondrial dynamics can cause axonal dysfunction and degeneration.
Finally, energy provided by mitochondria is another important feature of axonal survival [29].
Axon-specific attenuation of energy production initiates a cascade of events culminating in axon degeneration [30]. Even temporally-restricted attenuation of mitochondrial respiration is sufficient to trigger Wallerian-like degeneration in mouse sciatic nerves [31]. Thus, mitochondrial energetics also play a key role in axon maintenance.
Taken together, an axon is heavily dependent on its mitochondria. These mitochondria must perform efficiently on all levels, and even small perturbations that affect morphology, transport, quality or energy will ultimately culminate in axon degeneration. It is therefore not surprising that impaired fitness of mitochondria has been described in several neurological diseases (see Table). However, it remains to be established whether mitochondrial dysfunctions are a cause or a consequence in those conditions.
1.2) Axoskeleton
The peripheral nervous system (PNS) is constantly exposed to mechanical stress, and traumatic brain injury affects axons in the central nervous system (CNS) (reviewed in [32]).
Furthermore, axons can grow at a rate ranging from 8 mm/day in vitro (Dorsal root ganglion (DRG) explants from rat embryos) to 3 cm/day in vivo (blue whales) – each day, without breaking [1,33]. It is quite remarkable how circuit-integrated axons undergo “stretch growth” to extend at seemingly impossible rates without the aid of chemical cues or even growth cones. As animals grow, the nervous system appears to rapidly expand purely by mechanical forces, yet, there are no signs of axon degeneration. How do axons maintain their structural integrity when they are mechanistically challenged?
The cytoskeleton plays a crucial role during axonal specification and growth [34,35], as well as in mature circuit-integrated axons. The shaft of an axon is stabilized by a remarkably complex structure, the cytoskeleton of the axon (axoskeleton). Traditionally, electron microscopy [36,37], and more recently super-resolution fluorescence microscopy ([38]**;
reviewed in [39]), helped to decipher the axoskeletal structure: components are organized in ring-like structures consisting of Actin/Adducin, which are interspersed by Spectrin tetramers.
This periodic structure is also called the periodic membrane skeleton (PMS) and is conserved among different cell types and species [40–42]. It allows axons to be highly elastic and bears a unique capacity to withstand stretch, compression, tension, and torsion [43–45].
Recently, observations in C. elegans show that axons in β-spectrin mutants spontaneously break and undergo degeneration in a movement dependent manner [46]. Similarly, the depletion of αII-Spectrin specifically in myelinated large-diameter axons in mice results in signs of axonopathy, as indicated by β-Amyloid precursor protein staining (β-APP), a sensitive method to detect early axonal damage [47]. Likewise, axons lacking α-Adducin undergo progressive enlargement and ultimately degenerate [48]. Conversely, in a model of Nerve Growth Factor (NGF) withdrawal, acute pharmacological treatment that stabilizes Actin filaments following NGF withdrawal ameliorates axon degeneration [49]. These findings highlight the importance of the periodic axoskeleton required for mechanical support for axon survival.
Besides its crucial function for the PMS, the axoskeleton also plays a critical role in the axon initial segment (AIS). There, it is important for neuronal polarity, axonal integrity and identity, and, ultimately, for brain development [47,50].
Another well characterized component of the axoskeleton are microtubules (MTs), which consist of α- and β-Tubulin dimers. They provide the basis for anterograde and retrograde axonal transport [51,52]. Beyond their requirement for axonal transport, MTs are also important for axon maintenance, espcially after stretch; the breakdown of MTs leads to the degeneration of the axon [53], though this degeneration may be due to the absence of soma-derived axonal transport. In addition, a recent observation in Drosophila supports the notion that actin is required for MT polymerization and maintenance of the axon. Defects in the PMS brought about by treating the axon with actin depolymerizing drugs, or directly by MT destabilizers, leads to MT breakdown and ultimately axonal loss [42].
These findings support the idea that within the axoskeleton there is a tight interplay between MTs and the PMS. While the PMS seems to be important for the stability of MTs [42], there is additional evidence that MT stability is essential for the periodicity of the axoskeleton [54].
Dissecting this tightly regulated interplay between MTs and PMS presents obvious difficulties, however, we now know that both components of the axoskeleton convey mechanical neuroprotection, and they are both therefore essential for axon survival. Furthermore, this is supported by examples of neurological conditions that are associated with mutations in components of the axoskeleton (see Table).
In conclusion, axonal intrinsic, local, survival mechanisms are heavily dependent on axonal mitochondria as well as on the mechanistic structure of the axoskeleton. It is quite remarkable that a common feature of both mechanisms is local translation of mRNAs. Local protein synthesis turns out not only to be crucial for the development and maintenance of the axon (reviewed in [55]*, and [13,56–62]**), but also for responding to axonal injury and initiating regeneration [63]**.
2) Glial-mediated extrinsic axonal support
The vast majority neuronal volume is taken up by the axon, and it is unlikely that the soma is able to provide the full support necessary for efficient axonal performance. In recent years it has been appreciated that surrounding glial cells provide structural and energetic supporter for axons. Below, we discuss important axon-extrinsic mechanisms that ensure axonal survival.
2.1) Glial nurturing
Myelin, a glial-specific lipid-rich substance surrounding the axon, is essential for electric insulation, and therefore proper nervous system function. Though myelination of axons evolved specifically in vertebrates, a morphologically distinct myelin-like ensheathment of axons evolved independently in arthropods [64].
Myelin was long considered to be a simple passive insulator, but recent reports revealed that it is essential for axonal survival (reviewed in [65]). Mice lacking specific myelin transmembrane proteins develop widespread axonal swellings and degenerate [66]. Similarly, mice and humans lacking proteolipid protein 1 (PLP1), a major myelin protein, develop length-dependent axonopathies [67,68]. Moreover, loss of myelin-associated glycoprotein (MAG), or 2,3-cyclic nucleotide phosphodiesterase (CNP), ultimately leads to progressive axon loss in both the PNS and the CNS [69–71]. These observations demonstrate that glial-specific components of myelin are essential for the survival of the axon.
In addition, glia play a fundamental role in the maturation of the axoskeleton, thereby imposing structural changes on the axon. As mentioned above, the periodic membrane skeleton (PMS) is not only present in axons of the CNS and PNS, but it is also found in glia. It is interesting that the axonal PMS is aligned with the glia PMS: at the node of Ranvier with Schwann cells in the PNS [40,72]**, and in the CNS where differentiating oligodendrocytes use an axoglial adhesion complex for anchoring to the axonal cytoskeleton [73,74]. Both processes are crucial for the formation of nodes. Depletion of glial-specific cytoskeletal proteins that are required for node formation and periodic cytoskeletal organization can result in axon degeneration ([42,45,75–77]; reviewed in [78]). For example, the absence of the nodal adhesion protein Neurofascin 186 results in the destabilization of nodes and axon degeneration, which is exacerbated when the paranodal adhesion molecule Neurofascin 155 is also absent specifically in glia [77]. Similarly, removal of Ankyrin G induces destabilization of the nodes of Ranvier, thus
resulting in axon degeneration [79]. These observations strongly support a neuroprotective role for the glial cytoskeleton in mediating axonal maintenance.
Though myelin and the glial cytoskeleton impact axon survival, recent observations have uncovered a role for these components in proper architecture of the axon bundle and function;
changes in myelination cause improper white matter structure, which is a hallmark of human neurodevelopmental and psychiatric disorders such as Autism Spectrum Disorders (ASD), Schizophrenia (SCZ) and Fragile X syndrome (FXS) [80–83]. The observation of differentially- expressed myelin proteins in SCZ patients supports the notion that functionally impaired oligodendrocytes cause axonal dysfunction [84,85]. This is supported by findings in FXS mice, where oligodendrocytes have altered myelin basic protein MBP [86] levels. Thus, myelination in oligodendrocytes is crucial for axonal function, and the attenuation thereof contributes to neurodevelopmental and psychiatric disorders.
In addition, other glial cell types are required for axonal structure and function. Microglia have been extensively studied in the context of axonal pruning and outgrowth, yet their requirement for axonal structure was less well understood. However, recent observations uncovered a role for microglia both in healthy brains and also in neurodevelopmental or neurodegenerative disorders (Autism Spectrum Disorders or Alzheimer’s disease, respectively [87]). Brains with depleted microglia contain defasciculated callosal axons [88], suggesting that microglia, the immune cells of the brain, are also required for the proper maintenance of axonal architecture.
Taken together, substantial findings have shown that a variety of glial cell types are critical for the maintenance, structure and function of axons. Moreover, analysis of human disease, combined with the development of robust animal models, have contributed to our understanding why and how glial-derived axonopathies occur (see Table).
2.2) Energetic and metabolic support
The maintenance of a long axon poses a bioenergetic challenge for the neuronal soma. Axonal transport and maintenance of sodium gradients necessary for action potentials both consume significant amounts of energy. Axonal transport is unlikely sufficient to replenish energy in axons far from the soma. Recently, specialized mechanisms of energy delivery necessary for axonal survival have emerged, including the so-called “axo-myelinic neurotransmission” (reviewed in [89]**). Axons that transmit electrical impulses release glutamate, which in turn activates NMDA and AMPA receptors in the surrounding myelin sheath and leads to an increase in myelin- intrinsic Ca2+ concentration, which triggers oligodendrocyte release of lactate [90–93]. Thus, myelin is able to sense and respond to axonal activity by providing energetic and metabolic support.
Oligodendrocytes express high levels of monocarboxylate transporter 1 (MCT1), the most abundant lactate transporter in the CNS, and axons express MCT2 [94]**. Importantly, oligodendrocyte-specific loss of MCT1 leads to axonal degeneration, furthering the idea that axons are energetically supported by surrounding glia [94]**. This is also suggested by visualizing ATP dynamics in electrically active axons, where ATP levels correlate with action potentials that are reduced when pyruvate/lactate metabolism is diminished [95]*. Thus, axon survival depends upon metabolic support provided by surrounding glia.
Glia play also a significant role in supporting neuronal energy metabolism. Glial-specific attenuation of glycolysis results in neurodegeneration in Drosophila [96]. However, axon
degeneration induced by impaired mitochondrial respiration specifically in glia remains controversial: For example, in the PNS, Schwann cell-specific mitochondrial deficits result in severe, progressive, peripheral neuropathy that is characterized by extensive axonal degeneration [97]; however, in the CNS, axons are unaffected [98]. It remains unclear why in mammals, glial-specific energetic perturbations in the PNS affect peripheral neurons and their axons, but this is not observed in the CNS. A possible reason could be that the energetic/metabolic role of Schwann cells to support axons in the PNS differs from that of oligodendrocytes in the CNS.
Lipid metabolism in glia represents another key element in axon support and maintenance.
This is not only because lipids represent almost the 70% of myelin, but also because they control insulation of the axon and therefore the generation of action potentials [99]. In a mouse model of peripheral neuropathy, increased β-oxidation of fatty acids specifically in glia leads to depletion of the myelin lipid component and axonal degeneration [97]. Similarly, perturbation of glial peroxisomal biogenesis results in myelin sheath degeneration, which is required for long- term axonal integrity [100]. Taken together, loss of glial energetic/metabolic support ultimately culminates in progressive axon degeneration, which has been observed both in human disease and animal models of neurodegenerative conditions (see Table). This emphasize the importance of the interplay between axons and glia.
Our understanding of glial-mediated metabolic and structural support for the axon – and thus axon preservation – is still in its infancy. We are just beginning to gain insight into these mechanisms. Further investigations are required, and these hold promise for the development of therapeutic targets. The manipulation glial support for axons may, therefore, eventually lead to the promotion of remyelination and the restoration of normal nerve function in patients suffering from glial-related peripheral neuropathies (Table).
Conclusion
Axons rely on soma-derived support mediated by axonal transport. Yet, over the last several years we have only begun to appreciate that other support mechanisms are equally important for the life of the axon. Here, we have discussed distinct axon intrinsic, as well as extrinsic, mechanisms that ensure axonal structure, function and survival. Mutations in genes whose products impact these mechanisms have also been linked to axonopathies in humans.
Therefore, it is important to understand how axons are supported and maintained throughout the life span of their host. The availability of robust disease models offers great opportunities for the identification of disease mechanisms and will open the door to preclinical studies.
There are other mechanisms we have not covered here. Among them are, for example, glial- derived extracellular vesicles (exosomes) that have the potential to deliver proteins, lipids and RNAs to axons, rendering them more resistant to stress [101]. In addition, glial-derived neurotrophic factors promote axonal stability and preservation, as has been observed in mutant mice lacking Neurotrophin-3 in which motor axons initially innervate muscles but then experience catastrophic breakdown of intramuscular nerve branches and axon terminals [102].
These examples highlight the fact that we still know very little about how axons are maintained : for months in flies, for years in mice, and for decades in humans.
Another issue we have not covered in depth here is autophagy and its derivatives (e.g.
mitophagy and lysophagy). While the link between autophagy and a variety of neurodegenerative diseases has been clearly established (see Table), it remains to be determined whether axon degeneration is a cause, or a consequence. Particularly in the context of the axon and its terminal, distinct observations have been made: mitophagy of damaged mitochondria can occur locally within axons [103], and depolarized mitochondria can also be transported towards the soma where degradation occurs [104,105]. In the latter case, axonal transport forms the basis for autophagy to ensure axon homeostasis by removing aging proteins and damaged organelles from the distal axon for degradation and recycling. Of course, the longer the axon becomes, the more likely it is vulnerable to such mechanisms and therefore must rely on soma-independent mechanisms.
Axon degeneration has been observed as an early feature in many neurological conditions, not only in neurodegenerative diseases, but also in neurodevelopmental disorders [106,107], traumatic brain injuries (reviewed in [32]) and diabetes-induced peripheral neuropathies (reviewed in [108]) (see Table). Finally, it remains to be established whether or not certain dysfunctions are the cause, or consequence, of specific axonopathies. We are just beginning to understand the underlying mechanisms, and so are now on the road toward being able to define potential targets for therapeutic intervention.
ACKNOWLEDGMENTS
We apologize to our colleagues whose work could not be included due to space restrictions.
This work was supported by the État de Vaud (University of Lausanne) to CB and LJN, NCCR Synapsy (51NF40-158776) to CB, Swiss National Science Foundation (SNSF) Assistant Professor Grant (176855) to LJN, Fonds Wetenschappelijk Onderzoek (FWO) aspirant fellowship to NDI, and Opening the Future (OTF, Belgium) to VM and CB.
RECOMMENDED READING
11 •• Misgeld T, Schwarz TL: Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture. Neuron 2017, 96:651–666.
In this review the authors cover to a large extent the mechanisms of mitochondrial homeostasis in axons fosuing on mitochondrial transport, fusion, fission, local protein synthesis and mitophagy.
13 •• Yoon BC, Jung H, Dwivedy A, O’Hare CM, Zivraj KH, Holt CE: Local translation of extranuclear lamin B promotes axon maintenance. Cell 2012, 148:752–64.
This paper unveils how localized mRNA translation plays a cruicial role in axon homeostasis.
The authors unexpectedly found that the nuclear protein lamin B2 was translated in axons in vivo, thereby promoting mitochondrial function and axon survival.
17 •• Sheng Z-H: The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring. Trends Cell Biol 2017, 27:403–416.
The authors review mitochondrial trafficking and anchoring in maintaining axonal homeostasis and function.
38 •• Xu K, Zhong G, Zhuang X: Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons. Science (80- ) 2013, 339:452–456.
The authors discovered a periodic, structural organisation of cytoskeletal actin, spectrin and associated proteins in axons. These periodical structures regulate specific distributions of membrane proteins, for example sodium channels, which correlate with the actin-spectrin rings.
57 •• Izumikawa K, Nobe Y, Yoshikawa H, Ishikawa H, Miura Y, Nakayama H, Nonaka T, Hasegawa M, Egawa N, Inoue H, et al.: TDP-43 stabilises the processing intermediates of mitochondrial transcripts. Sci Rep 2017, 7:7709.
This publication describes a novel role for TDP-43 in maintaining mitochondria homeostasis.
TDP-43 accumulates inside mitochondria, and regulates the expression of mitochondria transcripts.
63. •• Terenzio M, Koley S, Samra N, Rishal I, Zhao Q, Sahoo PK, Urisman A, Marvaldi L, Oses-Prieto JA, Forester C, et al.: Locally translated mTOR controls axonal local translation in nerve injury. Science 2018, 359:1416–1421.
The authors found that mTOR mRNA is axonaly localized and orchestrates local translation both in physiological conditions and after injury. These findings highlight the importance of
mTOR mRNA transport and synthesis in axons and the spatiotemporal regulation of its pathways.
72 •• D’Este E, Kamin D, Balzarotti F, Hell SW: Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy. Proc Natl Acad Sci 2017, 114:E191–E199.
The authors describe the nanoscale organisation of 12 glial and axonal proteins at the nodes of Ranviers. The analysis revealed a specific structural and aligned organisation of proteins between glial and axonal cytoskeleton.
89 •• Micu I, Plemel JR, Caprariello A V., Nave K-A, Stys PK: Axo-myelinic neurotransmission: a novel mode of cell signalling in the central nervous system. Nat Rev Neurosci 2017, 19:49–58.
This review discusses recent findings of the dynamic communication between axons and myelin-forming olygodendrocytes, with a particular focus on metabolic support.
94 • Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A, Jin L, Zhang P-W, et al.: Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 2012, 487:443–8.
The authors elucidate the mechanisms of the astrocyte-neuron lactate shunt, by which oligodendroglia support neurons. Oligodendroglia express high levels of MCT1, the principal metabolic transmembrane transporter of lactate to axons.
95 • Trevisiol A, Saab AS, Winkler U, Marx G, Imamura H, Möbius W, Kusch K, Nave K-A, Hirrlinger J: Monitoring ATP dynamics in electrically active white matter tracts. Elife 2017, 6:e24241.
The authors show that ATP homeostasis correlates with action potentials, which is dependent on glia lactate metabolism.
55 • Cioni J-M, Koppers M, Holt CE: Molecular control of local translation in axon development and maintenance. Curr Opin Neurobiol 2018, 51:86–94.
This review discusses the mechanisms of local protein synthesis in axons, and how it regulates axonal development, stability, homeostasis, shape, and survival.
REFERENCES
1. Smith DH: Stretch growth of integrated axon tracts: extremes and exploitations.
Prog Neurobiol 2009, 89:231–9.
2. Wedel MJ: A Monument of Inefficiency: The Presumed Course of the Recurrent Laryngeal Nerve in Sauropod Dinosaurs. Acta Palaeontol Pol 2012, 57:251–256.
3. De Vos KJ, Grierson AJ, Ackerley S, Miller CCJ: Role of Axonal Transport in Neurodegenerative Diseases. Annu Rev Neurosci 2008, 31:151–173.
4. Polilov AA: The smallest insects evolve anucleate neurons. Arthropod Struct Dev 2012, 41:29–34.
5. Bittner GD: Long-term survival of anucleate axons and its implications for nerve regeneration. Trends Neurosci 1991, 14:188–193.
6. Ross TL, Govind CK, Kirk MD: Neuromuscular regeneration by buccal motoneuron B15 after peripheral nerve crush in Aplysia californica. J Neurophysiol 1994, 72:1897–1910.
7. Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, et al.: dSarm/Sarm1 is required for activation of an injury- induced axon death pathway. Science 2012, 337:481–4.
8. Xiong X, Hao Y, Sun K, Li J, Li X, Mishra B, Soppina P, Wu C, Hume RI, Collins CA: The Highwire Ubiquitin Ligase Promotes Axonal Degeneration by Tuning Levels of Nmnat Protein. PLoS Biol 2012, 10:e1001440.
9. Neukomm LJ, Burdett TC, Seeds AM, Hampel S, Coutinho-Budd JC, Farley JE, Wong J, Karadeniz YB, Osterloh JM, Sheehan AE, et al.: Axon Death Pathways Converge on Axundead to Promote Functional and Structural Axon Disassembly. Neuron 2017, 95:78–91.e5.
10. Alvarez J: The autonomous axon: a model based on local synthesis of proteins. Biol Res 2001, 34:103–109.
11. Misgeld T, Schwarz TL: Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture. Neuron 2017, 96:651–666.
12. Rawson RL, Yam L, Weimer RM, Bend EG, Hartwieg E, Horvitz HR, Clark SG, Jorgensen EM: Axons degenerate in the absence of mitochondria in C. elegans.
Curr Biol 2014, 24:760–5.
13. Yoon BC, Jung H, Dwivedy A, O’Hare CM, Zivraj KH, Holt CE: Local translation of extranuclear lamin B promotes axon maintenance. Cell 2012, 148:752–64.
14. Cosker KE, Pazyra-Murphy MF, Fenstermacher SJ, Segal RA: Target-derived neurotrophins coordinate transcription and transport of Bclw to prevent axonal degeneration. Ann Intern Med 2013, 158:5195–5207.
15. Misgeld T, Kerschensteiner M, Bareyre FM, Burgess RW, Lichtman JW: Imaging axonal transport of mitochondria in vivo. Nat Methods 2007, 4:559–561.
16. Spillane M, Ketschek A, Merianda TT, Twiss JL, Gallo G: Mitochondria coordinate sites of axon branching through localized intra-axonal protein synthesis. Cell Rep 2013, 5:1564–75.
17. Sheng Z-H: The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring. Trends Cell Biol 2017, 27:403–416.
18. Niescier RF, Kwak SK, Joo SH, Chang KT, Min K-T: Dynamics of Mitochondrial Transport in Axons. Front Cell Neurosci 2016, 10:123.
19. Yu Y, Lee H-C, Chen K-C, Suhan J, Qiu M, Ba Q, Yang G: Inner membrane fusion mediates spatial distribution of axonal mitochondria. Sci Rep 2016, 6:18981.
20. Stowers RS, Megeath LJ, Górska-Andrzejak J, Meinertzhagen IA, Schwarz TL: Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 2002, 36:1063–77.
Charlton MP, Atwood HL, Zinsmaier KE: The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses. Neuron 2005, 47:379–93.
22. Fang Y, Soares L, Teng X, Geary M, Bonini NM: A novel Drosophila model of nerve injury reveals an essential role of Nmnat in maintaining axonal integrity. Curr Biol 2012, 22:590–5.
23. Iijima-Ando K, Sekiya M, Maruko-Otake A, Ohtake Y, Suzuki E, Lu B, Iijima KM: Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer’s Disease-Related Tau Phosphorylation Via PAR-1. PLoS Genet 2012, 8:e1002918.
24. Iijima-Ando K, Hearn SA, Shenton C, Gatt A, Zhao L, Iijima K: Mitochondrial Mislocalization Underlies Aβ42-Induced Neuronal Dysfunction in a Drosophila Model of Alzheimer’s Disease. PLoS One 2009, 4:e8310.
25. Schrepfer E, Scorrano L: Mitofusins, from Mitochondria to Metabolism. Mol Cell 2016, 61:683–694.
26. Misko AL, Sasaki Y, Tuck E, Milbrandt J, Baloh RH: Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration. J Neurosci 2012, 32:4145–55.
27. Berthet A, Margolis EB, Zhang J, Hsieh I, Zhang J, Hnasko TS, Ahmad J, Edwards RH, Sesaki H, Huang EJ, et al.: Loss of mitochondrial fission depletes axonal
mitochondria in midbrain dopamine neurons. J Neurosci 2014, 34:14304–17.
28. Shields LY, Kim H, Zhu L, Haddad D, Berthet A, Pathak D, Lam M, Ponnusamy R, Diaz- Ramirez LG, Gill TM, et al.: Dynamin-related protein 1 is required for normal
mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons.
Cell Death Dis 2015, 6:e1725–e1725.
29. Campbell G, Mahad DJ: Mitochondrial dysfunction and axon degeneration in progressive multiple sclerosis. FEBS Lett 2018, 592:1113–1121.
30. LoPachin RM, Lehning EJ: Mechanism of Calcium Entry during Axon Injury and Degeneration. Toxicol Appl Pharmacol 1997, 143:233–244.
31. Alvarez S, Moldovan M, Krarup C: Acute energy restriction triggers Wallerian degeneration in mouse. Exp Neurol 2008, 212:166–178.
32. Hill CS, Coleman MP, Menon DK: Traumatic Axonal Injury: Mechanisms and Translational Opportunities. Trends Neurosci 2016, 39:311–324.
33. Pfister BJ, Iwata A, Meaney DF, Smith DH: Extreme stretch growth of integrated axons. J Neurosci 2004, 24:7978–83.
34. Bradke F, Dotti CG: The role of local actin instability in axon formation. Science 1999, 283:1931–4.
35. Donnelly CJ, Park M, Spillane M, Yoo S, Pacheco A, Gomes C, Vuppalanchi D, McDonald M, Kim HH, Kim HK, et al.: Axonally synthesized β-actin and GAP-43 proteins support distinct modes of axonal growth. J Neurosci 2013, 33:3311–22.
36. Hirokawa N: Cross-linker system between neurofilaments, microtubules, and membranous organelles in frog axons revealed by the quick-freeze, deep-etching method. J Cell Biol 1982, 94:129–42.
37. Schnapp BJ, Reese TS: Cytoplasmic structure in rapid-frozen axons. J Cell Biol 1982, 94:667–9.
38. Xu K, Zhong G, Zhuang X: Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons. Science (80- ) 2013, 339:452–456.
39. Leterrier C, Dubey P, Roy S: The nano-architecture of the axonal cytoskeleton. Nat Rev Neurosci 2017, 18:713–726.
40. D’Este E, Kamin D, Velte C, Göttfert F, Simons M, Hell SW: Subcortical cytoskeleton periodicity throughout the nervous system. Sci Rep 2016, 6:1–8.
41. He J, Zhou R, Wu Z, Carrasco MA, Kurshan PT, Farley JE, Simon DJ, Wang G, Han B, Hao J, et al.: Prevalent presence of periodic actin–spectrin-based membrane
skeleton in a broad range of neuronal cell types and animal species. Proc Natl Acad Sci 2016, 113:6029–6034.
42. Qu Y, Hahn I, Webb SED, Pearce SP, Prokop A: Periodic actin structures in neuronal axons are required to maintain microtubules. Mol Biol Cell 2017, 28:296–308.
43. Smith DH, Wolf JA, Meaney DF: A New Strategy to Produce Sustained Growth of Central Nervous System Axons: Continuous Mechanical Tension. Tissue Eng 2001, 7:131–139.
44. Fournier AJ, Hogan JD, Rajbhandari L, Shrestha S, Venkatesan A, Ramesh KT:
Changes in Neurofilament and Microtubule Distribution following Focal Axon Compression. PLoS One 2015, 10:e0131617.
45. Krieg M, Stühmer J, Cueva JG, Fetter R, Spilker K, Cremers D, Shen K, Dunn AR, Goodman MB: Genetic defects in β-spectrin and tau sensitize C. elegans axons to movement-induced damage via torque-tension coupling. Elife 2017, 6.
46. Hammarlund M, Jorgensen EM, Bastiani MJ: Axons break in animals lacking β- spectrin. J Cell Biol 2007, 176:269–275.
47. Huang CY-M, Zhang C, Ho TS-Y, Oses-Prieto J, Burlingame AL, Lalonde J, Noebels JL, Leterrier C, Rasband MN: αII Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function. J Neurosci 2017, 37:11311–11322.
48. Leite SC, Sampaio P, Sousa VF, Nogueira-Rodrigues J, Pinto-Costa R, Peters LL, Brites P, Sousa MM: The Actin-Binding Protein α-Adducin Is Required for Maintaining Axon Diameter. Cell Rep 2016, 15:490–498.
49. Unsain N, Bordenave MD, Martinez GF, Sami J, von Bilderling C, Barabas FM, Masullo LA, Johnstone AD, Barker PA, Mariano B, et al.: Remodeling of the Actin/Spectrin Membrane-associated Periodic Skeleton, Growth Cone Collapse and F-Actin Decrease during Axonal Degeneration. Sci Rep 2018, 8:3007.
50. Hedstrom KL, Ogawa Y, Rasband MN: AnkyrinG is required for maintenance of the axon initial segment and neuronal polarity. J Cell Biol 2008, 183:635–40.
51. Nirschl JJ, Ghiretti AE, Holzbaur ELF: The impact of cytoskeletal organization on the local regulation of neuronal transport. Nat Rev Neurosci 2017, 18:585–597.
52. Gumy LF, Hoogenraad CC: Local mechanisms regulating selective cargo entry and long-range trafficking in axons. Curr Opin Neurobiol 2018, 51:23–28.
53. Tang-Schomer MD, Patel AR, Baas PW, Smith DH: Mechanical breaking of
microtubules in axons during dynamic stretch injury underlies delayed elasticity, microtubule disassembly, and axon degeneration. FASEB J 2010, 24:1401–1410.
54. Zhong G, He J, Zhou R, Lorenzo D, Babcock HP, Bennett V, Zhuang X: Developmental mechanism of the periodic membrane skeleton in axons. Elife 2014, 3:e04581.
55. Cioni J-M, Koppers M, Holt CE: Molecular control of local translation in axon development and maintenance. Curr Opin Neurobiol 2018, 51:86–94.
56. Wang W, Wang L, Lu J, Siedlak SL, Fujioka H, Liang J, Jiang S, Ma X, Jiang Z, Da Rocha EL, et al.: The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat Med 2016, 22:869–878.
57. Izumikawa K, Nobe Y, Yoshikawa H, Ishikawa H, Miura Y, Nakayama H, Nonaka T, Hasegawa M, Egawa N, Inoue H, et al.: TDP-43 stabilises the processing
intermediates of mitochondrial transcripts. Sci Rep 2017, 7:7709.
58. Coyne AN, Siddegowda BB, Estes PS, Johannesmeyer J, Kovalik T, Daniel SG, Pearson A, Bowser R, Zarnescu DC: Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis. J Neurosci 2014, 34:15962–74.
59. Leung K-M, van Horck FP, Lin AC, Allison R, Standart N, Holt CE: Asymmetrical β-actin
Neurosci 2006, 9:1247–1256.
60. Piper M, Anderson R, Dwivedy A, Weinl C, van Horck F, Leung KM, Cogill E, Holt C:
Signaling Mechanisms Underlying Slit2-Induced Collapse of Xenopus Retinal Growth Cones. Neuron 2006, 49:215–228.
61. Wu KY, Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER, Jaffrey SR: Local translation of RhoA regulates growth cone collapse. Nature 2005, 436:1020–1024.
62. Yao J, Sasaki Y, Wen Z, Bassell GJ, Zheng JQ: An essential role for β-actin mRNA localization and translation in Ca2+-dependent growth cone guidance. Nat Neurosci 2006, 9:1265–1273.
63. Terenzio M, Koley S, Samra N, Rishal I, Zhao Q, Sahoo PK, Urisman A, Marvaldi L, Oses-Prieto JA, Forester C, et al.: Locally translated mTOR controls axonal local translation in nerve injury. Science 2018, 359:1416–1421.
64. Hartline DK: What is myelin? Neuron Glia Biol 2008, 4:153.
65. Nave K-A: Myelination and support of axonal integrity by glia. Nature 2010, 468:244– 252.
66. Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, Schneider A, Zimmermann F, McCulloch M, Nadon N, et al.: Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 1998, 280:1610–3.
67. Edgar JM, McLaughlin M, Yool D, Zhang S-C, Fowler JH, Montague P, Barrie JA, McCulloch MC, Duncan ID, Garbern J, et al.: Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J Cell Biol 2004, 166:121–31.
68. Garbern JY, Yool DA, Moore GJ, Wilds IB, Faulk MW, Klugmann M, Nave K-A, Sistermans EA, van der Knaap MS, Bird TD, et al.: Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal
degeneration in the absence of demyelination and inflammation. Brain 2002, 125:551–61.
69. Fruttiger M, Montag D, Schachner M, Martini R: Crucial Role for the Myelin-associated Glycoprotein in the Maintenance of Axon-Myelin Integrity. Eur J Neurosci 1995, 7:511–515.
70. Yin X, Crawford TO, Griffin JW, Tu P h, Lee VM, Li C, Roder J, Trapp BD: Myelin-
associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J Neurosci 1998, 18:1953–62.
71. Lappe-Siefke C, Goebbels S, Gravel M, Nicksch E, Lee J, Braun PE, Griffiths IR, Nave K- A: Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet 2003, 33:366–374.
72. D’Este E, Kamin D, Balzarotti F, Hell SW: Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy. Proc Natl Acad Sci 2017, 114:E191–E199.
73. Sherman DL, Brophy PJ: Mechanisms of axon ensheathment and myelin growth. Nat Rev Neurosci 2005, 6:683–690.
74. Brivio V, Faivre-Sarrailh C, Peles E, Sherman DL, Brophy PJ: Assembly of CNS Nodes of Ranvier in Myelinated Nerves Is Promoted by the Axon Cytoskeleton. Curr Biol 2017, 27:1068–1073.
75. Lorenzo DN, Li M, Mische SE, Armbrust KR, Ranum LPW, Hays TS: Spectrin mutations that cause spinocerebellar ataxia type 5 impair axonal transport and induce
neurodegeneration in Drosophila. J Cell Biol 2010, 189:143–58.
76. Takagishi Y, Katanosaka K, Mizoguchi H, Murata Y: Disrupted axon-glia interactions at the paranode in myelinated nerves cause axonal degeneration and neuronal cell death in the aged Caspr mutant mouse shambling. Neurobiol Aging 2016, 43:34–46.
77. Taylor AM, Saifetiarova J, Bhat MA: Postnatal Loss of Neuronal and Glial
Neurofascins Differentially Affects Node of Ranvier Maintenance and Myelinated Axon Function. Front Cell Neurosci 2017, 11:11.
78. Pan S, Chan JR: Regulation and dysregulation of axon infrastructure by myelinating glia. J Cell Biol 2017, 216:3903–3916.
79. Saifetiarova J, Taylor AM, Bhat MA: Early and Late Loss of the Cytoskeletal
Scaffolding Protein, Ankyrin G Reveals Its Role in Maturation and Maintenance of Nodes of Ranvier in Myelinated Axons. J Neurosci 2017, 37:2524–2538.
80. Deoni SCL, Zinkstok JR, Daly E, Ecker C, Williams SCR, Murphy DGM, Murphy DGM:
White-matter relaxation time and myelin water fraction differences in young adults with autism. Psychol Med 2015, 45:795–805.
81. Travers BG, Tromp DPM, Adluru N, Lange N, Destiche D, Ennis C, Nielsen JA, Froehlich AL, Prigge MBD, Fletcher P, et al.: Atypical development of white matter
microstructure of the corpus callosum in males with autism: a longitudinal investigation. Mol Autism 2015, 6:15.
82. Lang DJM, Yip E, MacKay AL, Thornton AE, Vila-Rodriguez F, MacEwan GW, Kopala LC, Smith GN, Laule C, MacRae CB, et al.: 48 echo T₂ myelin imaging of white matter in first-episode schizophrenia: evidence for aberrant myelination. NeuroImage Clin 2014, 6:408–14.
83. Swanson MR, Wolff JJ, Shen MD, Styner MA, Estes AM, Gerig G, McKinstry RC, Botteron KN, Piven J, Hazlett HC, et al.: Development of white matter circuitry in infants with fragile X syndrome. Under Embargo 2018, 48:174–182.
84. Cassoli JS, Guest PC, Malchow B, Schmitt A, Falkai P, Martins-de-Souza D: Disturbed macro-connectivity in schizophrenia linked to oligodendrocyte dysfunction: from structural findings to molecules. npj Schizophr 2015, 1:15034.
85. Roussos P, Haroutunian V: Schizophrenia: susceptibility genes and oligodendroglial and myelin related abnormalities. Front Cell Neurosci 2014, 8:5.
86. Pacey LKK, Xuan ICY, Guan S, Sussman D, Henkelman RM, Chen Y, Thomsen C, Hampson DR: Delayed myelination in a mouse model of fragile X syndrome. Hum Mol Genet 2013, 22:3920–3930.
87. Salter MW, Stevens B: Microglia emerge as central players in brain disease. Nat Med 2017, 23:1018–1027.
88. Pont-Lezica L, Beumer W, Colasse S, Drexhage H, Versnel M, Bessis A: Microglia shape corpus callosum axon tract fasciculation: functional impact of prenatal inflammation. Eur J Neurosci 2014, 39:1551–1557.
89. Micu I, Plemel JR, Caprariello A V., Nave K-A, Stys PK: Axo-myelinic
neurotransmission: a novel mode of cell signalling in the central nervous system.
Nat Rev Neurosci 2017, 19:49–58.
90. Saab AS, Tzvetavona ID, Trevisiol A, Baltan S, Dibaj P, Kusch K, Möbius W, Goetze B, Jahn HM, Huang W, et al.: Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism. Neuron 2016, 91:119–132.
91. Káradóttir R, Cavelier P, Bergersen LH, Attwell D: NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 2005, 438:1162–1166.
92. Burzomato V, Frugier G, Pérez-Otaño I, Kittler JT, Attwell D: The receptor subunits generating NMDA receptor mediated currents in oligodendrocytes. J Physiol 2010, 588:3403–14.
93. Micu I, Plemel JR, Lachance C, Proft J, Jansen AJ, Cummins K, van Minnen J, Stys PK:
The molecular physiology of the axo-myelinic synapse. Exp Neurol 2016, 276:41–50.
94. Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A, Jin L, Zhang P-W, et al.: Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 2012, 487:443–8.
Hirrlinger J: Monitoring ATP dynamics in electrically active white matter tracts. Elife 2017, 6:e24241.
96. Volkenhoff A, Weiler A, Letzel M, Stehling M, Klämbt C, Schirmeier S: Glial glycolysis is essential for neuronal survival in drosophila. Cell Metab 2015, 22:437–447.
97. Viader A, Sasaki Y, Kim S, Strickland A, Workman CS, Yang K, Gross RW, Milbrandt J:
Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron 2013, 77:886–98.
98. Fünfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, Brinkmann BG, Kassmann CM, Tzvetanova ID, Möbius W, et al.: Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 2012, 485:517–521.
99. Chrast R, Saher G, Nave K-A, Verheijen MHG: Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models. J Lipid Res 2011, 52:419–34.
100. Kassmann CM, Quintes S, Rietdorf J, Möbius W, Sereda MW, Nientiedt T, Saher G, Baes M, Nave K-A: A role for myelin-associated peroxisomes in maintaining paranodal loops and axonal integrity. FEBS Lett 2011, 585:2205–2211.
101. Frühbeis C, Fröhlich D, Kuo WP, Krämer-Albers E-M: Extracellular vesicles as mediators of neuron-glia communication. Front Cell Neurosci 2013, 7:182.
102. Woolley AG, Sheard PW, Duxson MJ: Neurotrophin-3 null mutant mice display a postnatal motor neuropathy. Eur J Neurosci 2005, 21:2100–2110.
103. Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL: Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol 2014, 206:655–70.
104. Cai Q, Zakaria HM, Simone A, Sheng Z-H: Spatial parkin translocation and
degradation of damaged mitochondria via mitophagy in live cortical neurons. Curr Biol 2012, 22:545–52.
105. Maday S, Wallace KE, Holzbaur ELF: Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. J Cell Biol 2012, 196:407– 17.
106. Ram S, Devapriya IA, Fenton G, Mcvay L, Nguyen D V, Tassone F, Maselli RA, Hagerman RJ: Axonal neuropathy in female carriers of the fragile X premutation with fragile x-associated tremor ataxia syndrome. Muscle Nerve 2015, 52:234–9.
107. Najjar S, Pearlman DM: Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res 2015, 161:102–112.
108. Cashman CR, Höke A: Mechanisms of distal axonal degeneration in peripheral neuropathies. Neurosci Lett 2015, 596:33–50.
109. Rizzo F, Ronchi D, Salani S, Nizzardo M, Fortunato F, Bordoni A, Stuppia G, Del Bo R, Piga D, Fato R, et al.: Selective mitochondrial depletion, apoptosis resistance, and increased mitophagy in human Charcot-Marie-Tooth 2A motor neurons. Hum Mol Genet 2016, 25:4266–4281.
110. Züchner S, Mersiyanova I V, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, 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.
111. Verhoeven K, Claeys KG, Züchner S, Schröder JM, Weis J, Ceuterick C, Jordanova A, Nelis E, De Vriendt E, Van Hul M, et al.: MFN2 mutation distribution and
genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 2006, 129:2093–2102.
112. Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, Ogawa M, Ishizaki Y, Kitamura T, Shozawa Y, et al.: Mitochondrial GTPase mitofusin 2 mutation in Charcot Marie Tooth neuropathy type 2A. Hum Genet 2005, 116:23–27.
113. Chung KW, Kim SB, Park KD, Choi KG, Lee JH, Eun HW, Suh JS, Hwang JH, Kim WK, Seo BC, et al.: Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 2006, 129:2103–2118.
114. Saitsu H, Tohyama J, Kumada T, Egawa K, Hamada K, Okada I, Mizuguchi T, Osaka H, Miyata R, Furukawa T, et al.: Dominant-Negative Mutations in α-II Spectrin Cause West Syndrome with Severe Cerebral Hypomyelination, Spastic Quadriplegia, and Developmental Delay. Am J Hum Genet 2010, 86:881–891.
115. Writzl K, Primec ZR, Stražišar BG, Osredkar D, Pečarič-Meglič N, Kranjc BS, Nishiyama K, Matsumoto N, Saitsu H: Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl with SPTAN1 mutation. Epilepsia 2012, 53:e106–e110.
116. Nguyen TT, Oh SS, Weaver D, Lewandowska A, Maxfield D, Schuler M-H, Smith NK, Macfarlane J, Saunders G, Palmer CA, et al.: Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proc Natl Acad Sci U S A 2014, 111:E3631-40.
117. Moller A, Bauer CS, Cohen RN, Webster CP, De Vos KJ: Amyotrophic lateral sclerosis-associated mutant SOD1 inhibits anterograde axonal transport of mitochondria by reducing Miro1 levels. Hum Mol Genet 2017, 26:4668–4679.
118. Zhang F, Wang W, Siedlak SL, Liu Y, Liu J, Jiang K, Perry G, Zhu X, Wang X: Miro1 deficiency in amyotrophic lateral sclerosis. Front Aging Neurosci 2015, 7:100.
119. Chen Y, Deng J, Wang P, Yang M, Chen X, Zhu L, Liu J, Lu B, Shen Y, Fushimi K, et al.:
PINK1 and Parkin are genetic modifiers for FUS-induced neurodegeneration. Hum Mol Genet 2016, 25:ddw310.
120. Rogers RS, Tungtur S, Tanaka T, Nadeau LL, Badawi Y, Wang H, Ni H-M, Ding W-X, Nishimune H: Impaired Mitophagy Plays a Role in Denervation of Neuromuscular Junctions in ALS Mice. Front Neurosci 2017, 11:473.
121. Taylor JP, Brown RH, Cleveland DW: Decoding ALS: from genes to mechanism.
Nature 2016, 539:197–206.
122. Evans CS, Holzbaur ELF: Autophagy and mitophagy in ALS. Neurobiol Dis 2018, doi:10.1016/J.NBD.2018.07.005.
123. Ikenaka K, Kawai K, Katsuno M, Huang Z, Jiang Y-M, Iguchi Y, Kobayashi K, Kimata T, Waza M, Tanaka F, et al.: dnc-1/dynactin 1 Knockdown Disrupts Transport of Autophagosomes and Induces Motor Neuron Degeneration. PLoS One 2013, 8:e54511.
124. Chia R, Chiò A, Traynor BJ: Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol 2018, 17:94–102.
125. Clark JA, Yeaman EJ, Blizzard CA, Chuckowree JA, Dickson TC: A Case for Microtubule Vulnerability in Amyotrophic Lateral Sclerosis: Altered Dynamics During Disease. Front Cell Neurosci 2016, 10:204.
126. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, Lavoie MJ, Schwarz TL: PINK1 and Parkin target miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 2011, 147:893–906.
127. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MMK, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, et al.: Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 2004, 304:1158–60.
128. 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.
129. Hsieh C-H, Shaltouki A, Gonzalez AE, Bettencourt da Cruz A, Burbulla LF, St. Lawrence E, Schüle B, Krainc D, Palmer TD, Wang X: Functional Impairment in Miro
Parkinson’s Disease. Cell Stem Cell 2016, 19:709–724.
130. Vital A, Meissner WG, Canron M-H, Martin-Negrier M-L, Bezard E, Tison F, Vital C: Intra- axonal protein aggregation in the peripheral nervous system. J Peripher Nerv Syst 2014, 19:44–49.
131. Koch JC, Bitow F, Haack J, d’Hedouville Z, Zhang J-N, Tönges L, Michel U, Oliveira LMA, Jovin TM, Liman J, et al.: Alpha-Synuclein affects neurite morphology,
autophagy, vesicle transport and axonal degeneration in CNS neurons. Cell Death Dis 2015, 6:e1811–e1811.
132. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, et al.: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997, 276:2045–7.
133. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schols L, Riess O: AlaSOPro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat Genet 1998, 18:106–108.
134. Mu L, Sobotka S, Chen J, Su H, Sanders I, Adler CH, Shill HA, Caviness JN, Samanta JE, Beach TG: Alpha-Synuclein Pathology and Axonal Degeneration of the
Peripheral Motor Nerves Innervating Pharyngeal Muscles in Parkinson Disease. J Neuropathol Exp Neurol 2013, 72:119–129.
135. Sadeghian M, Mastrolia V, Rezaei Haddad A, Mosley A, Mullali G, Schiza D, Sajic M, Hargreaves I, Heales S, Duchen MR, et al.: Mitochondrial dysfunction is an important cause of neurological deficits in an inflammatory model of multiple sclerosis. Sci Rep 2016, 6:1–14.
136. Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, et al.: Mitochondrial dysfunction as a cause of axonal
degeneration in multiple sclerosis patients. Ann Neurol 2006, 59:478–489.
137. Wolswijk G, Balesar R: Changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis. Brain 2003, 126:1638–1649.
138. Howell OW, Palser A, Polito A, Melrose S, Zonta B, Scheiermann C, Vora AJ, Brophy PJ, Reynolds R: Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain 2006, 129:3173–3185.
139. Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG: Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci U S A 2004, 101:8168–73.
140. Trapp BD, Nave K-A: Multiple Sclerosis: An Immune or Neurodegenerative Disorder? Annu Rev Neurosci 2008, 31:247–269.
141. Ferreirinha F, Quattrini A, Pirozzi M, Valsecchi V, Dina G, Broccoli V, Auricchio A, Piemonte F, Tozzi G, Gaeta L, et al.: Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport. J Clin Invest 2004, 113:231–42.
142. Denton KR, Xu C, Shah H, Li X-J: Modeling Axonal Defects in Hereditary Spastic Paraplegia with Human Pluripotent Stem Cells. Front Biol (Beijing) 2016, 11:339–354.
143. Yin X, Kidd GJ, Ohno N, Perkins GA, Ellisman MH, Bastian C, Brunet S, Baltan S, Trapp BD: Proteolipid protein-deficient myelin promotes axonal mitochondrial
dysfunction via altered metabolic coupling. J Cell Biol 2016, 215:531–542.
144. Courchesne SL, Karch C, Pazyra-Murphy MF, Segal RA: Sensory neuropathy attributable to loss of Bcl-w. J Neurosci 2011, 31:1624–34.
145. Shidara Y, Hollenbeck PJ: Defects in mitochondrial axonal transport and membrane potential without increased reactive oxygen species production in a Drosophila model of Friedreich ataxia. J Neurosci 2010, 30:11369–78.
146. Alexander C, Votruba M, Pesch UEA, Thiselton DL, Mayer S, Moore A, Rodriguez M,
Kellner U, Leo-Kottler B, Auburger G, et al.: OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 2000, 26:211–215.
147. Delettre C, Lenaers G, Griffoin J-M, Gigarel N, Lorenzo C, Belenguer P, Pelloquin L, Grosgeorge J, Turc-Carel C, Perret E, et al.: Nuclear gene OPA1, encoding a
mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 2000, 26:207–210.
148. Shirendeb UP, Calkins MJ, Manczak M, Anekonda V, Dufour B, McBride JL, Mao P, Reddy PH: Mutant huntingtin’s interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington’s disease. Hum Mol Genet 2012, 21:406–420.
149. Jodeiri Farshbaf M, Ghaedi K: Huntington’s Disease and Mitochondria. Neurotox Res 2017, 32:518–529.
150. Scott R, Sánchez-Aguilera A, van Elst K, Lim L, Dehorter N, Bae SE, Bartolini G, Peles E, Kas MJH, Bruining H, et al.: Loss of Cntnap2 Causes Axonal Excitability Deficits, Developmental Delay in Cortical Myelination, and Abnormal Stereotyped Motor Behavior. Cereb Cortex 2017, doi:10.1093/cercor/bhx341.
151. Roussos P, Katsel P, Davis KL, Bitsios P, Giakoumaki SG, Jogia J, Rozsnyai K, Collier D, Frangou S, Siever LJ, et al.: Molecular and Genetic Evidence for Abnormalities in the Nodes of Ranvier in Schizophrenia. Arch Gen Psychiatry 2012, 69:7.
152. Liska A, Bertero A, Gomolka R, Sabbioni M, Galbusera A, Barsotti N, Panzeri S, Scattoni ML, Pasqualetti M, Gozzi A: Homozygous Loss of Autism-Risk Gene CNTNAP2 Results in Reduced Local and Long-Range Prefrontal Functional Connectivity.
Cereb Cortex 2018, 28:1141–1153.
153. Peñagarikano O, Geschwind DH: What does CNTNAP2 reveal about autism spectrum disorder? Trends Mol Med 2012, 18:156–63.
154. Zerbi V, Ielacqua GD, Markicevic M, Haberl MG, Ellisman MH, A-Bhaskaran A, Frick A, Rudin M, Wenderoth N: Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories. Cereb Cortex 2018, 28:2495–2506.
Figure Legends
Figure 1. The longest cell in the history of life. Axons of neurons innervating muscles in blue whales reach up to 30m in length. For example, an axon of a 1 m long neuron can be up to 20.000x longer than its soma (around 50µm).
Figure 2. Soma-independent axonal maintenance mechanisms. Local mechanisms allow axons to respond dynamically to environmental challenges and thereby guarantee stability. Our review focuses on four of the major soma-independent mechanisms that ensure axon maintenance and function: mitochondrial and axoskeletal support, as well as glial-derived energetic support and nurturing (green, red, blue and yellow, respectively).
Table 1. Axonal survival mechanisms in disease. Defects in axon maintenance lead to axonal degeneration in several neurological disorders. Here we listed some examples of disease and disease models, where abnormalities in mechanisms of axonal survival result in axonal degeneration. Soma independent axonal maintenance mechanisms are color-coded as in Figure 2: mitochondrial and axoskeletal support, as well as glial-derived energetic support and nurturing (green, red, blue and yellow, respectively). Abbreviations: induced pluripotent stem cells (iPSCs).
Soma: 1x
Axon: up to 20.000x
Figure 1.
Figure 2.
Mitochondria Axoskeleton
Glial Support Glia Nurturing
* Local protein synthesis
* Motility
* Quality control
* Energy production
* Structural support
* Transport
* Local protein synthesis
* Myelin ensheatment
* Axoglial adhesion complex
* Energetic and metabolic supply
* Action potential propagation
Disease Mechanism Protein Disease model Human disease
Charcot-Marie-Tooth disease
Mitochondria: mitophagy PINK1
Motor neurons (iPSCs) [109] [109]
Mitochondria: mitophagy Parkin
Mitochondria: fusion Mitofusin 2 Cultured sensory neurons [26] [110–113]
West Syndrome Axoskeleton: PMS αll-Spectrin Mouse [47] [114,115]
Amyotrophic Lateral Sclerosis (ALS)
Mitochondria: energetic support, protein synthesis Complex I Mouse [56] [56]
Mitochondria: mobility Miro Mouse [116–118] [118]
Mitochondria: mobility and mitophagy PINK, Parkin and Miro Drosophila [119]
Mitochondria: mitophagy Ɨ PINK and Parkin Mouse [120]
Mitochondria: mitophagy Ɨ Autophagy
Ubiquitin-binding proteins
(SQSTM1, OPTN) [121,122]
Axoskeleton: Retrograde transport Ɨ
Autophagy Dynactin C. elegans [123] [122,124]
Axoskeleton: microtubule stability SOD1, TDP-43, TUBA4A, Mouse, Drosophila and Neuronal culture [125]
Axoskeleton: microtubule stability
Protein synthesis MAP1B Drosophila [58] [58]
Glia energetic support MCT1 Mouse and Spinal cord culture [94] [94]
Alzheimer’s Disease (AD) Mitochondria: mobility Miro and Milton Drosophila [23]
Parkinson’s disease (PD)
Mitochondria: mitophagy PINK1 $ Drosophila and Mouse [126] [127]
Mitochondria: mitophagy Parkin $ Drosophila and Mouse [103,126] [128]
Mitochondria: mobility Miro and LRRK2 Neurons (iPSCs), Fibroblast and
Drosophila [129] [129]
Axoskeleton: microtubule transport Ubiquitin and Tau [130]
Vesicle transport Φ α-Synuclein Rat [131] [132–134]
Multiple Sclerosis(MS)
Mitochondria: energetic support Complex IV Mouse [135] [29,136]
Glia nurturing: node of Ranvier
CASPR - [137]
Neurofascins - [138]
Sodium channels - [139]
Glia nurturing: myelin Myelin-associated glycoprotein
(MAG) Mouse [70,140]
Glia nurturing: myelin Cnp1 Mouse [71,140]
Glia nurturing: myelin Myelin membrane Proteolipids
(PLP and DM20) Mouse [66,140]
