Publicly available ex vivo transcriptomics datasets to explore CNS physiology and neurodegeneration: state of the art and perspectives

The central nervous system (CNS) is characterized by an intricate composition of diverse cell types, including neurons and glia cells (astrocytes, oligodendrocytes, and microglia), whose functions may differ along time, between sexes and upon pathology. The advancements in high-throughput transcriptomics are providing fundamental insights on cell phenotypes, so that molecular codes and instructions are ever more described for CNS physiology and neurodegeneration. To facilitate the search of relevant information, this review provides an overview of key CNS transcriptomics studies ranging from CNS development to ageing and from physiology to pathology as defined for five neurodegenerative disorders and their relative animal models, with a focus on molecular descriptions whose raw data were publicly available. Accurate phenotypic descriptions of cellular states correlate with functional changes and this knowledge may support research devoted to the development of therapeutic strategies supporting CNS repair and function

Author Correction:Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

The original version of this Article contained a typographical error in the spelling of the author Eliana M Coccia, which was incorrectly given as Eliana Coccia. This has now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Material files

Dysregulation of MS risk genes and pathways at distinct stages of disease

OBJECTIVE: To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions. METHODS: We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining. RESULTS: Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage–specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS. CONCLUSIONS: Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways

the heritage of glatiramer acetate and its use in multiple sclerosis

Multiple sclerosis (MS) is a chronic and progressively debilitating disease of the central nervous system. Treatment of MS involves disease-modifying therapies (DMTs) to reduce the incidence of relapses and prevent disease progression. Glatiramer acetate (Copaxone®) was the first of the currently approved DMTs to be tested in human subjects, and it is still considered a standard choice for first-line treatment. The mechanism of action of glatiramer acetate appears to be relatively complex and has not been completely elucidated, but it is likely that it involves both immunomodulating and neuroprotective properties. The efficacy of glatiramer acetate 20 mg/mL once daily as first-line treatment in relapsing-remitting MS is well established, with ample evidence of efficacy from both placebo-controlled and active-comparator controlled clinical trials as well as real-world studies. There is also a considerable body of evidence indicating that the efficacy of glatiramer acetate is maintained in the long term. Clinical trial and real-world data have also consistently shown glatiramer acetate to be safe and well tolerated. Notably, glatiramer acetate has a good safety profile in women planning a pregnancy, and is not associated with foetal toxicity. Until recently, glatiramer acetate was only approved as 20 mg/mL once daily, but a new formulation with less frequent administration, 40 mg/mL three times weekly, has been developed and is now approved in many countries, including Italy. This review examines the mechanism of action, clinical efficacy, safety and tolerability of glatiramer acetate to provide suggestions for optimizing the use of this drug in the current MS therapeutic scenario

Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes

Demyelination is a key pathogenic feature of multiple sclerosis (MS). Here, we evaluated the astrocyte contribution to myelin loss and focused on the neurotrophin receptor TrkB, whose up-regulation on the astrocyte finely demarcated chronic demyelinated areas in MS and was paralleled by neurotrophin loss. Mice lacking astrocyte TrkB were resistant to demyelination induced by autoimmune or toxic insults, demonstrating that TrkB signaling in astrocytes fostered oligodendrocyte damage. In vitro and ex vivo approaches highlighted that astrocyte TrkB supported scar formation and glia proliferation even in the absence of neurotrophin binding, indicating TrkB transactivation in response to inflammatory or toxic mediators. Notably, our neuropathological studies demonstrated copper dysregulation in MS and model lesions and TrkB-dependent expression of copper transporter (CTR1) on glia cells during neuroinflammation. In vitro experiments evidenced that TrkB was critical for the generation of glial intracellular calcium flux and CTR1 up-regulation induced by stimuli distinct from neurotrophins. These events led to copper uptake and release by the astrocyte, and in turn resulted in oligodendrocyte loss. Collectively, these data demonstrate a pathogenic demyelination mechanism via the astrocyte release of copper and open up the possibility of restoring copper homeostasis in the white matter as a therapeutic target in MS

Shared molecular and functional frameworks among five complex human disorders: a comparative study on interactomes linked to susceptibility genes

Background: Genome-wide association studies (gwas) are invaluable in revealing the common variants predisposing to complex human diseases. Yet, until now, the large volumes of data generated from such analyses have not been explored extensively enough to identify the molecular and functional framework hosting the susceptibility genes. Methodology/Principal Findings: We investigated the relationships among five neurodegenerative and/or autoimmune complex human diseases (Parkinson’s disease-Park, Alzheimer’s disease-Alz, multiple sclerosis-MS, rheumatoid arthritis-RA and Type 1 diabetes-T1D) by characterising the interactomes linked to their gwas-genes. An initial study on the MS interactome indicated that several genes predisposing to the other autoimmune or neurodegenerative disorders may come into contact with it, suggesting that susceptibility to distinct diseases may converge towards common molecular and biological networks. In order to test this hypothesis, we performed pathway enrichment analyses on each disease interactome independently. Several issues related to immune function and growth factor signalling pathways appeared in all autoimmune diseases, and, surprisingly, in Alzheimer’s disease. Furthermore, the paired analyses of disease interactomes revealed significant molecular and functional relatedness among autoimmune diseases, and, unexpectedly, between T1D and Alz. Conclusions/Significance: The systems biology approach highlighted several known pathogenic processes, indicating that changes in these functions might be driven or sustained by the framework linked to genetic susceptibility. Moreover, th

Honeybee floral constancy and pollination efficiency in sunflower (Hellianthus annuus) crops for hybrid seed production.

Honeybee Apis mellifera are considered essential pollinators in sunflower (Hellianthus annuus) crops for hybrid seed production where they have to transfer pollen from male fertile (MF) to male sterile cultivars (MS). Despite their biased preference for specific resources defined as floral constancy, it is unknown how they behave in hybrid sunflower seed crops exhibiting a noticeable dimorphism between parental lines. We studied honeybee foraging behavior in sunflower crop fields that exhibited a variable dimorphism among parental lines. Our results suggest low honeybee efficiency in terms of foraging flights between parental lines, since lower switching frequencies from MF to MS lines was observed for cultivars with increasing dimorphisms. Moreover, we also captured bees on MS capitula and at the hives to quantify the sunflower pollen grains adhered to their bee bodies with the aim to determine mechanisms responsible for the transfer of pollen between parental lines in cultivars with dimorphisms. Results show that honeybees located at the hive entrance, performing guarding and/or food receiving tasks, could act as agents facilitating pollen transfer between returning foragers and those that take off. This issue could partially compensated the low honeybee pollinating efficiency in terms of flights between parental lines.Fil: Susic Martín, Cinthia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Farina, Walter Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin

Treatment with glatiramer acetate induces specific IgG4 antibodies in multiple sclerosis patients

We analysed the humoral immune response to glatiramer acetate (GA, Copaxone) in 20 multiple sclerosis patients treated with GA, 20 patients not treated with GA and 20 normal control subjects. Using an ELISA for detection of total GA-reactive immunoglobulins (all isotypes), all treated patients but also 3/20 untreated and 8/20 healthy subjects scored positive at 1:20 plasma dilutions. At higher dilutions, 5/20 treated patients and two healthy donors had relatively high levels of anti-GA antibodies. Isotype and IgG subclass analysis revealed that the two antibody-positive normal subjects had IgM and small titers of IgG1 or IgG2 antibodies. In contrast, 18 of 20 GA-treated patients, had low but significant titers of GA- reactive IgG4 antibodies. This finding is consistent with the previously described GA-mediated induction of T-helper 2 (TH2)- like regulatory T cells. (C) 2002 Elsevier Science B.V All rights reserved