Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy.

BackgroundMultiple system atrophy (MSA) is a neurodegenerative disease characterized by parkinsonism, ataxia and dysautonomia. Histopathologically, the hallmark of MSA is the abnormal accumulation of alpha-synuclein (α-syn) within oligodendroglial cells, leading to neuroinflammation, demyelination and neuronal death. Currently, there is no disease-modifying treatment for MSA. In this sense, we have previously shown that next-generation active vaccination technology with short peptides, AFFITOPEs®, was effective in two transgenic models of synucleinopathies at reducing behavioral deficits, α-syn accumulation and inflammation.ResultsIn this manuscript, we used the most effective AFFITOPE® (AFF 1) for immunizing MBP-α-syn transgenic mice, a model of MSA that expresses α-syn in oligodendrocytes. Vaccination with AFF 1 resulted in the production of specific anti-α-syn antibodies that crossed into the central nervous system and recognized α-syn aggregates within glial cells. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn, reduced demyelination in neocortex, striatum and corpus callosum, and reduced neurodegeneration. Clearance of α-syn involved activation of microglia and reduced spreading of α-syn to astroglial cells.ConclusionsThis study further validates the efficacy of vaccination with AFFITOPEs® for ameliorating the neurodegenerative pathology in synucleinopathies

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluati

L'infirmier en réanimation

International audienc

L'infirmier en réanimation

International audienc

α5, α3, and Non-α3: three clustered avian genes encoding neuronal nicotinic acetylcholine receptor-related subunits

In vertebrates, neuronal nicotinic acetylcholine receptors (nAChRs) assemble in an unknown stoichiometry from two homologous subunits, an α and a non-α. How large is the repertoire of these subunits and how many subtypes of functionally different nAChRs can they constitute? We found in the avian genome a cluster of three closely linked genes spanning 28 kilobase pairs and encoding three proteins, nα3, α3, and α5, that have the features expected of neuronal nAChR subunits. Gene nα3 lies 5' of α3 (whose role in cholinoception has already been established) and is transcribed from the same DNA strand, whereas α5 lies 3' of α3 and is transcribed from the opposite DNA strand. The structure of the nα3 and α5 genes consists of six exons with precisely conserved splice sites and is identical to the structure of the previously characterized avian neuronal receptor subunit genes α2, α3, α4, and nα1. α3, nα3, and α5 transcripts are rare in the central nervous system, but α3 and nα3 are readily detectable in embryonic superior cervical and ciliary ganglia. In order to assay function, the gene encoding nα3 and the cDNAs encoding α3, α4, α5, and nα1 were subcloned into an expression vector, and the constructs were injected into Xenopus oocyte nuclei, either singly or in pairwise combinations of one α and one non-α. One to five days later, ACh sensitivity of the injected oocytes was examined in voltage clamp. The nα3 gene and nα1 cDNA elicited assembly of nAChRs when coinjected with α3 or α4 cDNA and the electrophysiological properties of the four pairwise combinations were significantly different. α5, however, did not direct the assembly of functional nAChRs when injected alone or in combination with nαl or nα3

A neuronal nicotinic acetylcholine receptor subunit (α7) is developmentally regulated and forms a homo-oligomeric channel blocked by α-BTX

cDNA and genomic clones encoding α7, a novel neuronal nicotinic acetylcholine receptor (nAChR) α subunit, were isolated and sequenced. The mature α7 protein (479 residues) has moderate homology with all other α and non-α nAChR subunits and probably assumes the same transmembrane topology. α7 transcripts transiently accumulate in the developing optic tectum between E5 and E16. They are present in both the deep and the superficial layers of E12 tectum. In Xenopus oocytes, the α7 protein assembles into a homo-oligomeric channel responding to acetylcholine and nicotine. The α7 channel desensitizes very rapidly, rectifies strongly above -20 mV, and is blocked by α-bungarotoxin. A bacterial fusion protein encompassing residues 124-239 of α7 binds labeled α-bungarotoxin. We conclude that α-bungarotoxin binding proteins in the vertebrate nervous system can function as nAChRs