Regeneration of adult mammalian central nervous system (CNS) axons is abortive, resulting in inability to recover function after CNS lesion, including spinal cord injury (SCI). Here, we show that the ...spiny mouse (Acomys) is an exception to other mammals, being capable of spontaneous and fast restoration of function after severe SCI, re-establishing hind limb coordination. Remarkably, Acomys assembles a scarless pro-regenerative tissue at the injury site, providing a unique structural continuity of the initial spinal cord geometry. The Acomys SCI site shows robust axon regeneration of multiple tracts, synapse formation, and electrophysiological signal propagation. Transcriptomic analysis of the spinal cord following transcriptome reconstruction revealed that Acomys rewires glycosylation biosynthetic pathways, culminating in a specific pro-regenerative proteoglycan signature at SCI site. Our work uncovers that a glycosylation switch is critical for axon regeneration after SCI and identifies β3gnt7, a crucial enzyme of keratan sulfate biosynthesis, as an enhancer of axon growth.
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•Acomys spontaneously regains motor and urinary functions following complete SCI•The Acomys SCI site shows abundant axon regeneration and nerve conduction•Acomys assembles a pro-regenerative environment with rewired ECM glycosylation•β3gnt7 is a novel axon regeneration enhancer
Nogueira-Rodrigues et al. report that Acomys can recover function after complete spinal cord injury (SCI), assembling a scarless tissue at the injury site, unlike other adult mammals. Transcriptomic analysis of the SCI site shows that injured Acomys builds a specific pro-regenerative proteoglycan signature with a unique glycosylation network.
Transthyretin enhances nerve regeneration Fleming, Carolina E; Saraiva, Maria J; Sousa, Mónica M
Journal of neurochemistry,
October 2007, Letnik:
103, Številka:
2
Journal Article
Recenzirano
Mutations in transthyretin (TTR) are associated with familial amyloid polyneuropathy, a neurodegenerative disorder characterized by TTR deposition in the PNS. The aim of this study was to unravel ...whether TTR has a role in nerve physiology that could account for its preferential accumulation in the PNS, when mutated. The sensorimotor performance of wild-type and TTR knockout (KO) littermate mice was compared and showed impairment in mice lacking TTR. Given the possibility that, upon regeneration, the consequences arising from TTR absence might be exacerbated, nerve crush was performed in both strains. TTR KO mice presented delayed functional recovery resulting from decreased number of myelinated and unmyelinated fibers. Moreover, in transgenic mice in a TTR KO background, expressing human TTR in neurons, this phenotype was rescued, reinforcing that TTR enhances nerve regeneration. In vitro assays showed that neurite outgrowth and extension were decreased in the absence of TTR, probably underlying the decreased number of regenerating axons in TTR KO mice. Our findings demonstrate that TTR participates in nerve physiology and that it enhances nerve regeneration. Moreover, the assignment of a TTR function in nerve biology and repair, may explain its preferential deposition, when mutated, in the PNS of familial amyloid polyneuropathy patients.
The growth rate of a population serves as a measure of its Darwinian fitness, while its sensitivity indicates the intensity of selection. Generally, the sensitivity of r decreases with age, resulting ...in an expected increase in population mortality over time. However, this does not hold true for many populations, especially those exhibiting negative senescence. Both evolutionary entropy and its sensitivity serve as complementary measures for assessing fitness and the intensity of selection. The sensitivity of entropy is typically a convex function of age, implying stronger selection pressures in younger and older age groups. We show that the sensitivity functions of entropy exhibit a greater range of behaviours compared to those of the growth rate alone. This strongly suggests that evolutionary entropy offers an extremely valuable measure for capturing the diversity in aging patterns within populations, complementing what can be captured by the growth rate alone.
Mutated transthyretin (TTR) causes familial amyloid polyneuropathy, a neurodegenerative disorder characterized by TTR deposition in the peripheral nervous system (PNS). The origin/reason for TTR ...deposition in the nerve is unknown. Here we demonstrate that both endogenous mouse TTR and TTR injected intravenously have access to the mouse sciatic nerve. We previously determined that in the absence of TTR, both neurite outgrowth in vitro and nerve regeneration in vivo were impaired. Reinforcing this finding, we now show that local TTR delivery to the crushed sciatic nerve rescues the regeneration phenotype of TTR knock-out (KO) mice. As the absence of TTR was unrelated to neuronal survival, we further evaluated the Schwann cell and inflammatory response to injury, as well as axonal retrograde transport, in the presence/absence of TTR. Only retrograde transport was impaired in TTR KO mice which, in addition to the neurite outgrowth impairment, might account for the decreased regeneration in this strain. Moreover, we show that in vitro, in dorsal root ganglia neurons, clathrin-dependent megalin-mediated TTR internalization is needed for TTR neuritogenic activity. Supporting this observation, we demonstrate that in vivo, decreased levels of megalin lead to decreased nerve regeneration and that megalin's action as a regeneration enhancer is dependent on TTR. In conclusion, our work unravels the mechanism of TTR action during nerve regeneration. Additionally, TTR presence in the nerve, as is here shown, may underlie its preferential deposition in the PNS of familial amyloid polyneuropathy patients.
While the benefits of nutrition and physical exercise are commonly studied separately, their concomitant integration has the potential to produce greater benefits in women than strategies focusing ...only on one or the other ...
Low energy availability (LEA) causes impaired physiological functioning. Cross-country running is a weight-sensitive sport, making athletes more prone to LEA. We aimed to estimate the prevalence of ...elite European cross-country athletes at risk of LEA using the LEA in Females Questionnaire (LEAF-Q) and to analyze demographic and physical characteristics that are associated with LEA. Athletes ≥ 18 years competing at the 26th European Cross-Country Championships (
= 602) were invited to complete a questionnaire (sociodemographic, training, anthropometric characteristics, and LEAF-Q). A total of 207 valid surveys were collected (83 females, 22.1 (4.0) years, and 124 males, 22.3 (4.1) years), and 16 surveys were excluded. A high prevalence of athletes at risk of LEA (64.3%) was observed, being higher in females than in males (79.5 and 54.0% respectively,
< 0.001). More than half of athletes (54.1%,
= 112) reported bowel movements once a week or more rarely, while 33 female athletes (41.3%) did not report normal menstruation. Overall, cross-country athletes are at high risk of LEA. Moreover, a high prevalence of gastrointestinal and menstrual impairments was reported. Hence, athletes should be followed by multidisciplinary teams to inform, prevent, and treat LEA and its effects.
In competitive events, athletes' performances can be affected by their food choices. In addition, nutrition labels are essential to sustain informed decisions and to allow athletes to comply with ...their dietary planning. Knowing what influences athletes' food choices will help to improve the food provision in future championships. Therefore, we aimed to study the factors influencing athletes' choices, their knowledge on nutrition labels, and their opinion on the food service at two European Athletics Championships. Questionnaires were completed by 339 athletes (57% males, 19.6 ± 1.3 years) competing at the 2019 European Athletics Under 20 and Under 23 Championships. Factors that may impact performance (time of the day and nutrient composition) were rated as important and very important by a higher percentage of athletes (78% and 74%, respectively) compared to the presence of teammates (32%) and the coach (23%). Among the athletes who knew what nutrition labels are (49%), 72% would like to have additional nutritional information in future championships. Furthermore, our study revealed that for most athletes (72%), food temperature is important or very important for food choices. Overall, food provision had positive results, but further research is needed to help organizers better tailor food provision to athletes' needs.
Lack of axon regeneration following spinal cord injury has been mainly ascribed to the inhibitory environment of the injury site, i.e., to chondroitin sulfate proteoglycans (CSPGs) and ...myelin-associated inhibitors (MAIs). Here, we used
shiverer
(shi) mice to assess axon regeneration following spinal cord injury in the presence of MAIs and CSPG but in the absence of compact myelin. Although in vitro shi neurons displayed a similar intrinsic neurite outgrowth to wild-type neurons, in vivo, shi fibers had increased regenerative capacity, suggesting that the wild-type spinal cord contains additional inhibitors besides MAIs and CSPG. Our data show that besides myelin protein, myelin lipids are highly inhibitory for neurite outgrowth and suggest that this inhibitory effect is released in the shi spinal cord given its decreased lipid content. Specifically, we identified cholesterol and sphingomyelin as novel myelin-associated inhibitors that operate through a Rho-dependent mechanism and have inhibitory activity in multiple neuron types. We further demonstrated the inhibitory action of myelin lipids in vivo, by showing that delivery of 2-hydroxypropyl-β-cyclodextrin, a drug that reduces the levels of lipids specifically in the injury site, leads to increased axon regeneration of wild-type (WT) dorsal column axons following spinal cord injury. In summary, our work shows that myelin lipids are important modulators of axon regeneration that should be considered together with protein MAIs as critical targets in strategies aiming at improving axonal growth following injury.
Abstract In Krabbe's disease (KD), a leukodystrophy caused by β-galactosylceramidase deficiency, demyelination and a myelin-independent axonopathy contributes to the severe neuropathology. Beyond ...axonopathy, we show that in Twitcher mice, a model of KD, a decreased number of axons both in the PNS and in the CNS, and of neurons in dorsal root ganglia (DRG), occurred before the onset of demyelination. Despite the early axonal loss, and although in vitro Twitcher neurites degenerated over time, Twitcher DRG neurons displayed an initial neurite overgrowth and, following sciatic nerve injury, Twitcher axons were regeneration-competent, at a time point where axonopathy was already ongoing. Psychosine, the toxic substrate that accumulates in KD, induced lipid raft clustering. At the mechanistic level, TrkA recruitment to lipid rafts was dysregulated in Twitcher neurons, and defective activation of the ERK1/2 and AKT pathways was identified. Besides defective recruitment of signaling molecules to lipid rafts, the early steps of endocytosis and the transport of endocytic and synaptic vesicles were impaired in Twitcher DRG neurons. Defects in axonal transport, specifically in the retrograde component, correlated with decreased levels of dynein, abnormal levels of post-translational tubulin modifications and decreased microtubule stability. The identification of the axonal defects that precede demyelination in KD, together with the finding that Twitcher axons are regeneration-competent when axonopathy is already installed, opens new windows of action to effectively correct the neuropathology that characterizes this disorder.
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