Highlights • Convergence between axon regeneration ability and abnormal synaptic structure and function. • Axon regeneration, neuronal circuit assembly and recovery of functions in the adult ...mammalian CNS are possible. • Combinatorial strategies provide hope for successfully regenerating and repairing the damaged CNS.
Failure of axon regeneration after central nervous system (CNS) injuries results in permanent functional deficits. Numerous studies in the past suggested that blocking extracellular inhibitory ...influences alone is insufficient to allow the majority of injured axons to regenerate, pointing to the importance of revisiting the hypothesis that diminished intrinsic regenerative ability critically underlies regeneration failure. Recent studies in different species and using different injury models have started to reveal important cellular and molecular mechanisms within neurons that govern axon regeneration. This review summarizes these observations and discusses possible strategies for stimulating axon regeneration and perhaps functional recovery after CNS injury.
The transcription factor p53 protects neurons from transformation and DNA damage through the induction of cell‐cycle arrest, DNA repair and apoptosis in a range of in vitro and in vivo conditions. ...Indeed, p53 has a crucial role in eliciting neuronal cell death during development and in adult organisms after exposure to a range of stressors and/or DNA damage. Nevertheless, accumulating evidence challenges this one‐sided view of the role of p53 in the nervous system. Here, we discuss how—unexpectedly—p53 can regulate the proliferation and differentiation of neural progenitor cells independently of its role in apoptosis, and p53 post‐translational modifications might promote neuronal maturation, as well as axon outgrowth and regeneration, following neuronal injury. We hope to encourage a more comprehensive view of the non‐apoptotic functions of p53 during neural development, and to warn against oversimplifications regarding its role in neurons. In addition, we discuss how further insight into the p53‐dependent modulation of these mechanisms is necessary to elucidate the decision‐making processes between neuronal cell death and differentiation during development, and between neuronal degeneration and axonal regeneration after injury.
Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of ...new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.
After central nervous system (CNS) injury, inhibitory factors in the lesion scar and poor axon growth potential prevent axon regeneration. Microtubule stabilization reduces scarring and promotes axon ...growth. However, the cellular mechanisms of this dual effect remain unclear. Here, delayed systemic administration of a blood-brain barrier–permeable microtubule-stabilizing drug, epothilone B (epoB), decreased scarring after rodent spinal cord injury (SCI) by abrogating polarization and directed migration of scar-forming fibroblasts. Conversely, epothilone B reactivated neuronal polarization by inducing concerted microtubule polymerization into the axon tip, which propelled axon growth through an inhibitory environment. Together, these drug-elicited effects promoted axon regeneration and improved motor function after SCI. With recent clinical approval, epothilones hold promise for clinical use after CNS injury.
Microvascular complications are often associated with slow and progressive damage of various organs. Pericytes are multi-functional mural cells of the microcirculation that control blood flow, ...vascular permeability and homeostasis. Whereas accumulating evidence suggests that these cells are also implicated in a variety of diseases, pericytes represent promising targets that can be manipulated for therapeutic gain. Here, we review the role of pericytes in angiogenesis, blood-brain barrier (BBB) function, neuroinflammation, tissue fibrosis, axon regeneration failure, and neurodegeneration. In addition, we outline strategies altering pericyte behavior to point out problems and promises for axon regeneration and central nervous system (CNS) repair following injury or disease.
Injured axons fail to regenerate in the adult CNS, which contrasts with their vigorous growth during embryonic development. We explored the potential of re-initiating axon extension after injury by ...reactivating the molecular mechanisms that drive morphogenetic transformation of neurons during development. Genetic loss- and gain-of-function experiments followed by time-lapse microscopy, in vivo imaging, and whole-mount analysis show that axon regeneration is fueled by elevated actin turnover. Actin depolymerizing factor (ADF)/cofilin controls actin turnover to sustain axon regeneration after spinal cord injury through its actin-severing activity. This pinpoints ADF/cofilin as a key regulator of axon growth competence, irrespective of developmental stage. These findings reveal the central role of actin dynamics regulation in this process and elucidate a core mechanism underlying axon growth after CNS trauma. Thereby, neurons maintain the capacity to stimulate developmental programs during adult life, expanding their potential for plasticity. Thus, actin turnover is a key process for future regenerative interventions.
Display omitted
•Elevated actin turnover is essential for regenerative growth•ADF/cofilin activity increases during conditioning-mediated regeneration•ADF/cofilin is necessary and sufficient for axon regeneration•The severing activity of ADF/cofilin is critical for axon regeneration
Tedeschi et al. identify ADF/cofilin as a key driver of axon regeneration in adult dorsal root ganglion neurons. Specifically, enhanced actin turnover by the ADF/cofilin severing function controls axon regeneration in the adult CNS.
Axon regeneration failure causes neurological deficits and long-term disability after spinal cord injury (SCI). Here, we found that the α2δ2 subunit of voltage-gated calcium channels negatively ...regulates axon growth and regeneration of corticospinal neurons, the cells that originate the corticospinal tract. Increased α2δ2 expression in corticospinal neurons contributed to loss of corticospinal regrowth ability during postnatal development and after SCI. In contrast, α2δ2 pharmacological blockade through gabapentin administration promoted corticospinal structural plasticity and regeneration in adulthood. Using an optogenetic strategy combined with in vivo electrophysiological recording, we demonstrated that regenerating corticospinal axons functionally integrate into spinal circuits. Mice administered gabapentin recovered upper extremity function after cervical SCI. Importantly, such recovery relies on reorganization of the corticospinal pathway, as chemogenetic silencing of injured corticospinal neurons transiently abrogated recovery. Thus, targeting α2δ2 with a clinically relevant treatment strategy aids repair of motor circuits after SCI.
PDF
