Wallerian degeneration is a widespread mechanism of programmed axon degeneration. In the three decades since the discovery of the Wallerian degeneration slow (Wld
) mouse, research has generated ...extensive knowledge of the molecular mechanisms underlying Wallerian degeneration, demonstrated its involvement in non-injury disorders and found multiple ways to block it. Recent developments have included: the detection of NMNAT2 mutations that implicate Wallerian degeneration in rare human diseases; the capacity for lifelong rescue of a lethal condition related to Wallerian degeneration in mice; the discovery of 'druggable' enzymes, including SARM1 and MYCBP2 (also known as PHR1), in Wallerian pathways; and the elucidation of protein structures to drive further understanding of the underlying mechanisms and drug development. Additionally, new data have indicated the potential of these advances to alleviate a number of common disorders, including chemotherapy-induced and diabetic peripheral neuropathies, traumatic brain injury, and amyotrophic lateral sclerosis.
Activation of the NAD hydrolase domain of Sarm1 mediates axonal degeneration caused by chemotherapy drugs, but the downstream events are unknown. In this issue, Li and colleagues (2021. J. Cell ...Biol.https://doi.org/10.1083/jcb.202106080) demonstrate that cADPR, a breakdown product of NAD, mediates paclitaxel-induced axonal degeneration by promoting influx of calcium into the axons.
Rodent models of nerve injury have increased our understanding of peripheral nerve regeneration, but clinical applications have been scarce, partly because such models do not adequately recapitulate ...the situation in humans. In human injuries, axons are often required to extend over much longer distances than in mice, and injury leaves distal nerve fibres and target tissues without axonal contact for extended amounts of time. Distal Schwann cells undergo atrophy owing to the lack of contact with proximal neurons, which results in reduced expression of neurotrophic growth factors, changes in the extracellular matrix and loss of Schwann cell basal lamina, all of which hamper axonal extension. Furthermore, atrophy and denervation-related changes in target tissues make good functional recovery difficult to achieve even when axons regenerate all the way to the target tissue. To improve functional outcomes in humans, strategies to increase the speed of axonal growth, maintain Schwann cells in a healthy, repair-capable state and keep target tissues receptive to reinnervation are needed. Use of rodent models of chronic denervation will facilitate our understanding of the molecular mechanisms of peripheral nerve regeneration and create the potential to test therapeutic advances.
Functional recovery after repair of peripheral nerve injury in humans is often suboptimal. Over the past quarter of a century, there have been significant advances in human nerve repair, but most of ...the developments have been in the optimization of surgical techniques. Despite extensive research, there are no current therapies directed at the molecular mechanisms of nerve regeneration. Multiple interventions have been shown to improve nerve regeneration in small animal models, but have not yet translated into clinical therapies for human nerve injuries. In many rodent models, regeneration occurs over relatively short distances, so the duration of denervation is short. By contrast, in humans, nerves often have to regrow over long distances, and the distal portion of the nerve progressively loses its ability to support regeneration during this process. This can be largely attributed to atrophy of Schwann cells and loss of a Schwann cell basal lamina tube, which results in an extracellular environment that is inhibitory to nerve regeneration. To develop successful molecular therapies for nerve regeneration, we need to generate animal models that can be used to address the following issues: improving the intrinsic ability of neurons to regenerate to increase the speed of axonal outgrowth; preventing loss of basal lamina and chronic denervation changes in the denervated Schwann cells; and overcoming inhibitory cues in the extracellular matrix.
Peripheral neuropathy is a common complication of a variety of diseases and treatments, including diabetes, cancer chemotherapy, and infectious causes (HIV, hepatitis C, and Campylobacter jejuni). ...Despite the fundamental difference between these insults, peripheral neuropathy develops as a combination of just six primary mechanisms: altered metabolism, covalent modification, altered organelle function and reactive oxygen species formation, altered intracellular and inflammatory signaling, slowed axonal transport, and altered ion channel dynamics and expression. All of these pathways converge to lead to axon dysfunction and symptoms of neuropathy. The detailed mechanisms of axon degeneration itself have begun to be elucidated with studies of animal models with altered degeneration kinetics, including the slowed Wallerian degeneration (WldS) and Sarm knockout animal models. These studies have shown axonal degeneration to occur through a programmed pathway of injury signaling and cytoskeletal degradation. Insights into the common disease insults that converge on the axonal degeneration pathway promise to facilitate the development of therapeutics that may be effective against other mechanisms of neurodegeneration.
Distal axon degeneration seen in many peripheral neuropathies is likely to share common molecular mechanisms with Wallerian degeneration. Although several studies in mouse models of peripheral ...neuropathy showed prevention of axon degeneration in the slow Wallerian degeneration (Wlds) mouse, the role of a recently identified player in Wallerian degeneration, Sarm1, has not been explored extensively. In this study, we show that mice lacking the Sarm1 gene are resistant to distal axonal degeneration in a model of chemotherapy induced peripheral neuropathy caused by paclitaxel and a model of high fat diet induced putative metabolic neuropathy. This study extends the role of Sarm1 to axon degeneration seen in peripheral neuropathies and identifies it as a likely target for therapeutic development.
Neurogenic atrophy refers to the loss of muscle mass and function that results directly from injury or disease of the peripheral nervous system. Individuals with neurogenic atrophy may experience ...reduced functional status and quality of life and, in some circumstances, reduced survival. Distinct pathological findings on muscle histology can aid in diagnosis of a neurogenic cause for muscle dysfunction, and provide indicators for the chronicity of denervation. Denervation induces pleiotypic responses in skeletal muscle, and the molecular mechanisms underlying neurogenic muscle atrophy appear to share common features with other causes of muscle atrophy, including activation of FOXO transcription factors and corresponding induction of ubiquitin-proteasomal and lysosomal degradation. In this review, we provide an overview of histologic features of neurogenic atrophy and a summary of current understanding of underlying mechanisms.
Mitochondrial dynamics and mitophagy have been linked to cardiovascular and neurodegenerative diseases. Here, we demonstrate that the mitochondrial division dynamin Drp1 and the Parkinson's ...disease‐associated E3 ubiquitin ligase parkin synergistically maintain the integrity of mitochondrial structure and function in mouse heart and brain. Mice lacking cardiac Drp1 exhibited lethal heart defects. In Drp1KO cardiomyocytes, mitochondria increased their connectivity, accumulated ubiquitinated proteins, and decreased their respiration. In contrast to the current views of the role of parkin in ubiquitination of mitochondrial proteins, mitochondrial ubiquitination was independent of parkin in Drp1KO hearts, and simultaneous loss of Drp1 and parkin worsened cardiac defects. Drp1 and parkin also play synergistic roles in neuronal mitochondrial homeostasis and survival. Mitochondrial degradation was further decreased by combination of Drp1 and parkin deficiency, compared with their single loss. Thus, the physiological importance of parkin in mitochondrial homeostasis is revealed in the absence of mitochondrial division in mammals.
Synopsis
In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease‐associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain.
Mitochondria divide in cardiomyocytes.
Drp1 deficiency causes mitochondrial dysfunction, lethal heart failure and neurodegeneration due to defects in mitophagy.
Mitochondria enlarge and accumulate ubiquitinated outer membrane proteins and mitophagy adaptor protein p62 independently of parkin.
Parkin is dispensable for mitochondrial respiration, heart function and neuronal survival in the presence of Drp1‐regulated mitophagy.
Simultaneous loss of Drp1 and parkin increases mitophagy defects.
In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease‐associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain.
•Summary of the programmed axon degeneration pathway.•Review of pathogenesis of CMT subtypes and programmed axon degeneration pathway.•Discussion of therapies based on programmed axon degeneration ...pathway in CMT.
The programmed axon degeneration pathway has emerged as an important process contributing to the pathogenesis of several neurological diseases. The most crucial events in this pathway include activation of the central executioner SARM1 and NAD+ depletion, which leads to an energetic failure and ultimately axon destruction. Given the prevalence of this pathway, it is not surprising that inhibitory therapies are currently being developed in order to treat multiple neurological diseases with the same therapy. Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of neurological diseases that may also benefit from this therapeutic approach. To evaluate the appropriateness of this strategy, the contribution of the programmed axon degeneration pathway to the pathogenesis of different CMT subtypes is being actively investigated. The subtypes CMT1A, CMT1B and CMT2D are the first to have been examined. Based on the results from these studies and advances in developing therapies to block the programmed axon degeneration pathway, promising therapeutics for CMT are now on the horizon.
Abstract Many diseases of the peripheral nervous system affect the function of Schwann cells. Recent developments in stem cell technology offer the opportunity to engineer stem cell derived glial ...cell populations that reveal essential phenotypic characteristics of Schwann cells including growth support and myelination of peripheral axons. Potential applications of these cells include its use as platform for human cell-based disease models as well as potential source for cell transplantation strategies. In this review we provide an update on the latest developments in engineering Schwann cells as diagnostic tools or for cell replacement therapies in peripheral neuropathic conditions. This article is part of a Special Issue entitled PSC and the brain.
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