Distinct changes in synaptic protein composition at neuromuscular junctions of extraocular muscles versus limb muscles of ALS donors

The pathophysiology of amyotrophic lateral sclerosis (ALS) is very complex and still rather elusive but in recent years evidence of early involvement of the neuromuscular junctions (NMJs) has accumulated. We have recently reported that the human extraocular muscles (EOMs) are far less affected than limb muscles at the end-stage of ALS from the same donor. The present study aimed to compare the differences in synaptic protein composition at NMJ and in nerve fibers between EOM and limb muscles from ALS donors and controls. Neurofilament light subunit and synaptophysin decreased significantly at NMJs and in nerve fibers in limb muscles with ALS whereas they were maintained in ALS EOMs. S100B was significantly decreased at NMJs and in nerve fibers in both EOMs and limb muscles of ALS donors, but other markers confirmed the presence of terminal Schwann cells in these NMJs. p75 neurotrophin receptor was present in nerve fibers but absent at NMJs in ALS limb muscles. The EOMs were able to maintain the integrity of their NMJs to a very large extent until the end-stage of ALS, in contrast to the limb muscles. Changes in Ca2+ homeostasis, reflected by altered S100B distribution, might be involved in the breakdown of nerve-muscle contact at NMJs in ALS

Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse.

The development of chemical synapses is regulated by interactions between pre- and postsynaptic cells. At the vertebrate skeletal neuromuscular junction, the organization of an acetylcholine receptor (AChR)-rich postsynaptic apparatus has been well studied. Much evidence suggests that the nerve-derived protein agrin activates muscle-specific kinase (MuSK) to cluster AChRs through the synapse-specific cytoplasmic protein rapsyn. But how postsynaptic differentiation is initiated, or why most synapses are restricted to an \u27end-plate band\u27 in the middle of the muscle remains unknown. Here we have used genetic methods to address these issues. We report that the initial steps in postsynaptic differentiation and formation of an end-plate band require MuSK and rapsyn, but are not dependent on agrin or the presence of motor axons. In contrast, the subsequent stages of synaptic growth and maintenance require nerve-derived agrin, and a second nerve-derived signal that disperses ectopic postsynaptic apparatus

Divergence Among an International Population of Trichophyton tonsurans Isolates

Trichophyton tonsurans is a widely distributed pathogen that demonstrates a significant degree of genetic and phenetic heterogeneity. To date, the degree of genetic relatedness among geographically segregated isolates has not been explored. This investigation evaluates the extent of genetic variation among an international population of T. tonsurans isolates and examines the relatedness of isolates within and between countries. Molecular strain typing was performed on 198 isolates obtained from 14 countries. A mixed-marker strategy utilizing 27 sequence variations in 13 gene loci was applied to all isolates and cluster analysis was performed to examine the relationship between strains. Phylogenetic analysis was used to corroborate the findings of the cluster analysis with T. equinum strains serving as an out-group. In total, 47 distinct strain types were identified represented by seven clusters and one singleton. There appeared to be a moderate degree of clustering among isolates obtained from North America, Asia and Australia, although European isolates were uniformly distributed among the majority of clusters. The degree of genetic variation observed in this study coupled with the geographic localization would support the argument for allopatric divergence within this species.Susan M. Abdel-Rahman, Takashi Sugita, Gloria M. González, David Ellis, Michalis Arabatzis, Loranne Vella-Zahra, Calude Viguié-Vallanet, Masataro Hiruma, J. Steven Leeder and Barry Preuet