Mechanisms of axon degeneration: From development to disease

Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Progress in Neurobiology (Impact Factor: 9.99). 11/2007; 83(3):174-91. DOI: 10.1016/j.pneurobio.2007.07.007
Source: PubMed


Axon degeneration is an active, tightly controlled and versatile process of axon segment self-destruction. Although not involving cell death, it resembles apoptosis in its logics. It involves three distinct steps: induction of competence in specific neurons, triggering of degeneration at defined axon segments of competent neurons, and rapid fragmentation and removal of the segments. The mechanisms that initiate degeneration are specific to individual settings, but the final pathway of pruning is shared; it involves microtubule disassembly, axon swellings, axon fragmentation, and removal of the remnants by locally recruited phagocytes. The tight regulatory properties of axon degeneration distinguish it from passive loss phenomena, and confer significance to processes that involve it. Axon degeneration has prominent roles in development, upon lesions and in disease. In development, it couples the progressive specification of neurons and circuits to the removal of defined axon branches. Competence might involve transcriptional switches, and local triggering can involve axon guidance molecules and synaptic activity patterns. Lesion-induced Wallerian degeneration is inhibited in the presence of Wld(S) fusion protein in neurons; it involves early local, and later, distal degeneration. It has recently become clear that like in other settings, axon degeneration in disease is a rapid and specific process, which should not be confused with a variety of disease-related pathologies. Elucidating the specific mechanisms that initiate axon degeneration should open up new avenues to investigate principles of circuit assembly and plasticity, to uncover mechanisms of disease progression, and to identify ways of protecting synapses and axons in disease.

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Available from: Smita Saxena,
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    • "Development of precise neuronal circuits often involves the formation of exuberant connections followed by degenerative events, such as neurite pruning, that may be subsequently followed by regrowth and the formation of new, adult specific, connections (Luo and O'Leary, 2005; Schuldiner and Yaron, 2015). Axon fragmentation during developmental axon pruning shares some mechanistic similarities with axon fragmentation and elimination in neurodegenerative diseases or adjustment of neuronal connections in response to injury (Hoopfer et al., 2006; Saxena and Caroni, 2007). Therefore, understanding the molecular and cellular mechanisms governing neuronal remodeling should provide us with a broader understanding of the mechanisms regulating axon fragmentation and elimination during development and disease. "
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    ABSTRACT: Holometabolous insects, including Drosophila melanogaster, undergo complete metamorphosis that includes a pupal stage. During metamorphosis, the Drosophila nervous system undergoes massive remodeling and growth, that include cell death and large-scale axon and synapse elimination as well as neurogenesis, developmental axon regrowth and formation of new connections. Neuronal remodeling is an essential step in the development of vertebrate and invertebrate nervous systems. Research on the stereotypic remodeling of Drosophila mushroom body (MB) γ neurons has contributed to our knowledge of the molecular mechanisms of remodeling but our knowledge of the cellular mechanisms remain poorly understood. A major hurdle in understanding various dynamic processes that occur during metamorphosis is the lack of time-lapse resolution. The pupal case and opaque fat bodies that enwrap the central nervous system (CNS) make live-imaging of the central brain in-vivo impossible. We have established an ex-vivo long-term brain culture system that supports the development and neuronal remodeling of pupal brains. By optimizing culture conditions and dissection protocols, we have observed development in culture at kinetics similar to what occurs in vivo. Using this new method, we have obtained the first time-lapse sequence of MB γ neurons undergoing remodeling in up to a single cell resolution. We found that axon pruning is initiated by blebbing, followed by one-two nicks that seem to initiate a more widely spread axon fragmentation. As such, we have set up some of the tools and methodologies needed for further exploration of the cellular mechanisms of neuronal remodeling, not limited to the MB. The long-term ex-vivo brain culture system that we report here could be used to study dynamic aspects of neurodevelopment of any Drosophila neuron.
    Frontiers in Cellular Neuroscience 08/2015; 9. DOI:10.3389/fncel.2015.00327 · 4.29 Impact Factor
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    • "During degeneration, the axon blebs and fragments. This blebbing and fragmentation is dependent on cytoskeletal disassembly and has been hypothesized to be controlled by factors that regulate microtubule stability, such as microtubule-associated proteins [3]. The downstream mechanisms that cause cytoskeletal degradation in axons have not been fully elucidated, but ultimately, cytoskeletal degradation appears to be a point of convergence for axon degeneration induced by a variety of mechanisms. "
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    ABSTRACT: Axon degeneration is a characteristic feature of multiple neuropathologic states and is also a mechanism of physiological neurodevelopmental pruning. The vast majority of in vivo studies looking at axon degeneration have relied on the use of classical silver degeneration stains, which have many limitations including lack of molecular specificity and incompatibility with immunolabeling methods. Because Wallerian degeneration is well known to involve cytoskeletal disassembly and because caspases are recently implicated in aspects of this process, we asked whether antibodies directed at caspase-generated neoepitopes of beta-actin and alpha-tubulin would be useful immunohistochemical markers of pathological and developmental axon degeneration. Here we demonstrate that several forms of axon degeneration involve caspase-mediated cleavage of these cytoskeletal elements and are well-visualized using this approach. We demonstrate the generation of caspase-induced neoepitopes in a) an in vitro neuronal culture model using nerve growth factor-deprivation-induced degeneration and b) an in vivo model using ethanol-induced neuronal apoptosis, and c) during normal developmental pruning and physiological turnover of neurons. Our findings support recent experimental data that suggests caspase-3 and caspase-6 have specific non-redundant roles in developmental pruning. Finally, these findings may have clinical utility, as these markers highlight degenerating neurites in human hypoxic-ischemic injury. Our work not only confirms a common downstream mechanism involved in axon degeneration, but also illuminates the potential utility of caspase-cleavage-neoepitope antibodies as markers of neurodegeneration.
    02/2014; 2(1):16. DOI:10.1186/2051-5960-2-16
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    • "One abundant type of neuronal remodeling is axon and dendrite pruning which involves the removal of exuberant connections in a tightly regulated process [1]. Axon pruning has been shown to share molecular similarities with axon degeneration following injury as well as ‘dying-back’ neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and the later stages of multiple sclerosis (MS) [1], [2]. Thus, uncovering the mechanisms of developmental axon pruning should shed light onto how axons are eliminated during development, disease and following injury. "
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    ABSTRACT: Axon pruning is an evolutionarily conserved strategy used to remodel neuronal connections during development. The Drosophila mushroom body (MB) undergoes neuronal remodeling in a highly stereotypical and tightly regulated manner, however many open questions remain. Although it has been previously shown that glia instruct pruning by secreting a TGF-β ligand, myoglianin, which primes MB neurons for fragmentation and also later engulf the axonal debris once fragmentation has been completed, which glia subtypes participate in these processes as well as the molecular details are unknown. Here we show that, unexpectedly, astrocytes are the major glial subtype that is responsible for the clearance of MB axon debris following fragmentation, even though they represent only a minority of glia in the MB area during remodeling. Furthermore, we show that astrocytes both promote fragmentation of MB axons as well as clear axonal debris and that this process is mediated by ecdysone signaling in the astrocytes themselves. In addition, we found that blocking the expression of the cell engulfment receptor Draper in astrocytes only affects axonal debris clearance. Thereby we uncoupled the function of astrocytes in promoting axon fragmentation to that of clearing axonal debris after fragmentation has been completed. Our study finds a novel role for astrocytes in the MB and suggests two separate pathways in which they affect developmental axon pruning.
    PLoS ONE 01/2014; 9(1):e86178. DOI:10.1371/journal.pone.0086178 · 3.23 Impact Factor
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