L’architecture et la fonction des fibres myélinisées sont dépendantes de l’établissement de contacts cellulaires finement réglés entre les membranes d’une même cellule gliale myélinisante, entre l’axone et les cellules gliales, et entre les cellules gliales et la matrice extracellulaire. Des composants protéiques majeurs de l’ensemble de ces contacts ont été identifiés ces dernières années. Des progrès importants ont notamment été faits dans l’identification de complexes moléculaires impliqués dans les contacts axo-gliaux au niveau des noeuds de Ranvier. Le rôle capital de certains composants des contacts dans le maintien de l’intégrité structurale et fonctionnelle des fibres a été démontré par la production de modèles murins. Dans certains cas, des mutations des gènes correspondants ont été identifiées chez des patients atteints de neuropathies périphériques telles que les maladies de Charcot-Marie-Tooth (CMT).
Abstract Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations of the survival motor neuron 1 gene ( SMN1 ). No curative treatment is available. Mutant mice carrying homozygous deletion of Smn exon 7 directed to neurons display a degenerative process of motor neurons similar to that found in human SMA. To test whether riluzole, which exhibits neurotrophic properties, might have a protective role in SMA, mutant mice were treated with it after the onset of the degenerative process. Riluzole improved median survival and exerted a protective effect against aberrant cytoskeletal organization of motor synaptic terminals but not against loss of proximal axons. These results demonstrate that the disease course of SMA can be attenuated after the onset of neuromuscular defects and may warrant further investigation in a therapeutic trial in SMA. Muscle Nerve 28: 432–437, 2003
Deletion of murine Smn exon 7, the most frequent mutation found in spinal muscular atrophy, has been directed to either both satellite cells, the muscle progenitor cells and fused myotubes, or fused myotubes only. When satellite cells were mutated, mutant mice develop severe myopathic process, progressive motor paralysis, and early death at 1 mo of age (severe mutant). Impaired muscle regeneration of severe mutants correlated with defect of myogenic precursor cells both in vitro and in vivo. In contrast, when satellite cells remained intact, mutant mice develop similar myopathic process but exhibit mild phenotype with median survival of 8 mo and motor performance similar to that of controls (mild mutant). High proportion of regenerating myofibers expressing SMN was observed in mild mutants compensating for progressive loss of mature myofibers within the first 6 mo of age. Then, in spite of normal contractile properties of myofibers, mild mutants develop reduction of muscle force and mass. Progressive decline of muscle regeneration process was no more able to counterbalance muscle degeneration leading to dramatic loss of myofibers. These data indicate that intact satellite cells remarkably improve the survival and motor performance of mutant mice suffering from chronic myopathy, and suggest a limited potential of satellite cells to regenerate skeletal muscle.
A thorough examination of the structure and plasticity of the neuromuscular system was performed in tenascin-C mutant mice deficient in tenascin-C. The study of the peripheral nerve revealed a number of abnormal features. In the motor nerve, numerous unmyelinated and myelinated fibers with degraded myelin were present. Schwann cell processes often enclosed degenerative terminals. Transgene (beta-galactosidase) expression analyzed at the ultrastructural level was found to be unequally distributed in the mutant's neuromuscular tissues. At the NMJ, preterminal disorganization was prevalent. Some axon terminals exhibited abnormal overgrowth. A surprising lack of beta-galactosidase expression at some cellular sites known to possess tenascin-C in wild type mice correlated best with marked changes in the cytoarchitecture of the peripheral nerve and NMJ. In some other -but not all- cellular sites which normally express the molecule, immunofluorescence analysis suggested the presence of significant but low levels of tenascin-C-like immunoreactivity together with beta-galactosidase expression. Messenger RNA detection by RT-PCR confirmed the presence of low amounts of tenascin-C mRNA in skeletal muscle suggesting that the mice deficient in tenascin-C are not complete knock-outs of this gene, but low-expression mutants. Following in vivo injections of botulinum type-A toxin, we observed a greatly reduced sprouting response of the motor nerves in tenascin-C mutant mice. We also observed that N-CAM and beta-catenin were overexpressed in the mutant. Our results suggest that tenascin-C is involved both in stabilization and in plasticity of the NMJ.
Myoneurin belongs to the BTB/POZ and zinc finger protein family whose members have been implicated in regulatory functions of gene expression. Myoneurin has been identified in various tissues, but muscle is a privileged site of myoneurin gene transcription. We examined the neuromuscular expression of myoneurin during development and after axotomy. Myoneurin expression is developmentally regulated in mouse muscle and appeared to be associated with neuromuscular junctions during the late embryonic period. Myoneurin is located in and around synaptic myonuclei in mouse and human adult muscle. The expression of myoneurin is dysregulated after nerve section. Thus, the restricted myoneurin expression in synaptic myonuclei appeared to be controlled by muscle electrical activity. Myoneurin is identified within the peripheral condensed chromatin and the euchromatin/heterochromatin regions, and thus fulfills structural and expression criteria to represent a synaptic gene regulator.
Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase-dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system.
