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Wallerian Degeneration of Injured Axons and Synapses Is Delayed By

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Wallerian Degeneration of Injured Axons and Synapses Is Delayed By Overview Introduction Wallerian Degeneration of Background Information Injured Axons and Synapses is Aims Delayed by a Ube4b/Nmnat Results Discussion Chimeric Gene Future Research Mack T, Reiner M, Beirowski B, Weiqian M, Emanuelli M, Wagner D, Thomson D, Gillingwater T, Court F, Conforti L, Questions Fernando F. S, Tarlton A, Andressen C, Addicks K, Magni G, Ribchester R. R, Perry V. H and Coleman M. P. Introduction - Background Introduction - Background Distal axons of injured neurons usually undergo Wallerian s degeneration 24-48 hours after injury. A candidate Wld gene was identified on In C57BL/Wlds mice, injured axons can survive several weeks chromosome 4 (mouse) following injury. This suggests that these mice have a protective mechanism specific to the It is a chimeric gene containing coding axons, and that this protective factor must be present in the axon prior to any injury occurring as the distal part of the axon is separated from the cell body regions for Ube4b/D4Cole1e in the mouse and cannot benefit from new protein synthesis. D4Cole1e was found to be equivalent to the Wallerian degeneration is implicated in several human neuropathologies. human enzyme Nmnat. These include ALS, multiple sclerosis and traumatic disorders such as injury to the spinal cord Both proteins were found to be expressed in An understanding of the mechanisms controlling the slow Wlds mice, strongly suggesting that this Wallerian degeneration exhibited by the C57BL/Wlds mouse could lead to the new therapeutic targets for such diseases. chimeric gene is the Wlds gene Introduction - Aims Transgenic Mice Generated Hypothesis: the Ube4b/Nmnat chimeric gene 4 lines of transgenic mice were generated for is the Wlds gene and produces the slow this study: 4839, 4830, 4858 and 4836. Wallerian degeneration phenotype observed In each line, the expression level of the in the mutant mice. chimeric gene had been altered. To test this, the chimeric gene was The lowest level was expressed in 4839; 4830 expressed in transgenic mice. and 4858 showed a medium level of gene Several strains of mice were produced, each with expression (only 4830 is further discussed in the a different expression level of the chimeric gene. paper); 4836 had the strongest expression which is almost identical to Wlds mouse. Results Results Structural Preservation of Transected Axons Structural preservation was investigated 3-5 days following a unilateral lesion to the sciatic nerve. Electron microscopy showed that the vast majority of axons in the 4836 mouse had preserved cytoskeletons 5 days after injury Successful replication of the Wlds phenotype. WT mice showed clear signs of degeneration in myelinated and unmyelinated axons. Partial protection was observed as expected in 4830 axons Results Results Functionally Competent Motor Axons and Synapses Tested whether the motor axons were still functional as well as structurally preserved. Using intracellular recordings, the response of the muscle to nerve stimulation and the generation of action potentials were recorded No evidence of motor axons still functioning in WT mice. In transgenic mice, there was evidence of functioning motor axons and synapses for at least three days after injury. In homozygous 4836 mice, nerve stimulation led to a functional response in 80% of muscle fibres 3 days after injury. In heterozygous 4836 mice and 4830 mice, the percentage of muscle fibres which responded to nerve stimulation after injury were significantly lower than the 4836 mouse, and the duration after injury which the axons and synapses appeared functional was also reduced. Results Results Functional motor axons and synapses were visualised using immunostaining methods Homozygous 4836 mice demonstrated synaptic vesicle recycling 5 days after injury, indicating synaptic transmission is still able to occur. Homozygous 4836 mice also showed a high proportion of endplates fully occupied 5 days after injury. Proportion of endplates occupied were reduced in hemizygous 4836 mice and in 4830 mice. Results Results Protection Depends on Wld Protein Expression Levels The level of Wld protein expression in the mutant strains was quantified using a Western blot analysis. Homozygous 4836 mutant mice showed similar expression of the protein to the Wlds mouse, again confirming that the Wlds phenotype was successfully recreated. Other strains showed dose-dependent expression of Wld protein. Homozygous 4836 mutant mice also demonstrated a higher proportion of intact axons 5 days after sciatic nerve lesion compared to other stains, which were visualised using electron microscopy. Results Results To further test how expression levels of Wld protein protects axons from degeneration, the degree of neurofilament degradation (measured by Western blot) and the number of intact axons (electron microscopy) were measured after 10- 14 days. In Wlds and homozygous 4836 mice, neurofilament degradation was less than that of other strains. In homozgous 4836 and Wlds mice, axon protection was significantly better than that of WT and other mutant strains. Results Results Wld is a Predominantly Nuclear Protein Wld protein was found to be localised in the nucleus of Wlds and transgenic mice, using immunostaining methods. It was not located in the nucleus of WT mice. There was no detection of Wld protein in the axons of any mouse strain. This study did not find evidence of Wld expression in glial cells, but previous studies have reported detecting Wld protein in Schwann cells using RT-PCR Wld may have roles other than axon protection in other cell types Results Results The Wld protein has Nmnat Enzyme Activity Intrinsic Nmnat activity was initially measured using recombinant protein expression and measuring the activity of the bacterial lysate. In Wlds mice, Nmnat levels were measured in brain homogenates and were found to be four times higher than the control. Total NAD+ levels were not significantly increased however, indicating that Wld protein increases Nmnat levels but not overall NAD+ levels. Discussion And Further Conclusions Research The paper concludes that the Ube4b/Nmnat The role of Ube4b and Nmnat chimeric gene has been successfully identified As the Wld protein is located in the nucleus, the actions as the Wld gene. of Ube4b and Nmnat may be influence downstream s regulatory pathways, which can then go on to directly The Wld phenotype was successfully recreated influence axon protective mechanisms. in the homozygous 4836 transgenic mouse. Ube4b is involved in ubiquitination processes may It was also shown that the level of expression of produce protective effects by influencing the stability of the Wld protein directly relates to the level of protein-protein interactions or RNA, or by affecting axon protection. nuclear transport. Nmnat levels in Wlds mice is increased, but NAD+ levels Wld protein was found to be localised in the remain similar to that of WT. This suggests that the nucleus and that it protects axons through an NAD+ is being metabolised. These metabolites may indirect mechanism involving other factors. produce neuroprotective effects. Discussion And Further Questions Research Wld Protein as a Therapeutic Target How could nuclear Wlds protect severed axons? What is the s significance of constant levels of NAD+? Is the ubiquitin-proteasome Wld phenotype is known to protect axons from system involved? toxic effects of vincristine. Nuclear Wlds most likely protects severed axons by altering Studies have also indicated that Wlds protects regulatory pathways prior to the axon being severed. against a mouse model of motor neurone disease. The constant NAD+ levels observed in Wlds mice indicate that a significant proportion of NAD+ is being metabolised. Metabolites From the identification of the Wld gene, and of NAD+ are known to exert both neuroprotective and neurotoxic through investigation into the mechanisms effects. through which Wld protein exerts its Ube4b is a multi-ubiquitinating enzyme. Although the full Ube4b neuroprotective effects, therapeutic targets for gene is not expressed in the chimeric gene, it is likely that the several neuropathologies could be identified. role of Ube4b in Wlds is likely to be similar to that of the regular enzyme. Therefore, there is a strong possibility that the ubiquitin- proteasome pathway is involved in the protection of axons; possibly through degrading proteins which produce or enhance the process of Wallerian degeneration Age-dependent synapse Outline withdrawal at axotomised neuromuscular junctions in Intro/background Wlds mutant and Aims/hypothesis Methods Ube4b/Nmnat Results transgenic mice Conclusion Thomas H. Gillingwater*†, Derek Thomson*†, Till G. A. Strengths/weaknesses Mack‡, Ellen M. Soffin*, Richard J. Mattison*, Michael P. Coleman‡ and Richard R. Ribchester* BBQs Journal of Physiology (2002), 543.3, pp. 739–755 DOI: 10.1113/jphysiol.2002.022343 Summary © The Physiological Society 2002 Mairi Laverty Background Aims and Hypothesis Wallerian degeneration: the molecular and cellular responses that are involved in the degeneration of distal axons and synaptic terminals after Previous controversy whether age affected lesion or injury the neuroprotective role of the Wlds gene Wlds mutation: overexpression of a chimeric Ube4b/Nmnat (Wld) gene that protects axons from Wallerian degeneration Aim: “to resolve the discrepancy between the Wlds mutation is inherited as a single autosomal dominant characteristic, by a gene located
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