No abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuron degeneration in motor cortex, brainstem and spinal cord. microRNAs (miRNAs) are small non-coding RNAs that bind complementary target sequences and modulate gene expression; they are key molecules for establishing a neuronal phenotype, and in neurodegeneration. Here we investigated neural miR-9, miR-124a, miR-125b, miR-219, miR-134, and cell cycle-related miR-19a and -19b, in G93A-SOD1 mouse brain in pre-symptomatic and late stage disease.ResultsExpression of miR-9, miR-124a, miR-19a and -19b was significantly increased in G93A-SOD1 whole brain at late stage disease compared to B6.SJL and Wt-SOD1 control brains. These miRNAs were then analyzed in manually dissected SVZ, hippocampus, primary motor cortex and brainstem motor nuclei in 18-week-old ALS mice compared to same age controls. In SVZ and hippocampus miR-124a was up-regulated, miR-219 was down-regulated, and numbers of neural stem progenitor cells (NSPCs) were significantly increased. In G93A-SOD1 brainstem motor nuclei and primary motor cortex, miR-9 and miR-124a were significantly up-regulated, miR-125b expression was also increased. miR-19a and -19b were up-regulated in primary motor cortex and hippocampus, respectively. Expression analysis of predicted miRNA targets identified miRNA/target gene pairs differentially expressed in G93A-SOD1 brain regions compared to controls.ConclusionsHierarchical clustering analysis, identifying two clusters of miRNA/target genes, one characterizing brainstem motor nuclei and primary motor cortex, the other hippocampus and SVZ, suggests that altered expression of neural and cell cycle-related miRNAs in these brain regions might contribute to ALS pathogenesis in G93A-SOD1 mice. Re-establishing their expression to normal levels could be a new therapeutic approach to ALS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0095-0) contains supplementary material, which is available to authorized users.

No abstract

Pathogen infections and dysregulated Toll-like receptor (TLR)-mediated innate immune responses are suspected to play key roles in autoimmunity. Among TLRs, TLR7 and TLR9 have been implicated in several autoimmune conditions, mainly because of their ability to promote abnormal B cell activation and survival. Recently, we provided evidence of Epstein-Barr virus (EBV) persistence and reactivation in the thymus of myasthenia gravis (MG) patients, suggesting an involvement of EBV in the intrathymic pathogenesis of the disease. Considerable data highlight the existence of pathogenic crosstalk among EBV, TLR7, and TLR9: EBV elicits TLR7/9 signaling, which in turn can enhance B cell dysfunction and autoimmunity. In this article, after a brief summary of data demonstrating TLR activation in MG thymus, we provide an overview on the contribution of TLR7 and TLR9 to autoimmune diseases and discuss our recent findings indicating a pivotal role for these two receptors, along with EBV, in driving, perpetuating, and/or amplifying intrathymic B cell dysregulation and autoimmune responses in MG. Development of therapeutic approaches targeting TLR7 and TLR9 signaling could be a novel strategy for treating the chronic inflammatory autoimmune process in myasthenia gravis.

No abstract

No abstract

These findings highlight the role that the ATP-binding cassette subfamily C member 6 haplotype may play in AZA drug response. In view of the significant effects and AZA intolerance, these novel SNPs should be taken into consideration in pharmacogenetic profiling for AZA.

Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare, early onset, autosomal recessive motor neuron disease characterized by progressive weakness and spasticity. Several mutations in the alsin 2 gene (ALS2) have been described in IAHSP patients; however, a relevant subset of patients is ALS2 mutationnegative, and pathogenic events causing the disease are unknown. The present study aimed at better understanding the molecular mechanisms underlying motor neuron loss in IAHSP patients by identifying microRNAs (miRNAs) potentially implicated in neuronal differentiation. Using the human induced pluripotent stem cell (iPSC) technology, we developed a patient-specific in vitro cellular model and performed miRNome profiling in fibroblasts, iPSCs and iPSCs-derived neurons obtained from an ALS2 mutation-negative IAHSP patient and a healthy control. The selected differentially expressed miRNAs were also analyzed in fibroblasts, iPSCs and iPSCs-derived neurons from two patients affected by other motor neuron diseases, two patients with other neurological disease, and three healthy controls. We found that miR-376a, miR-432 and miR-451a expression was altered in cell cultures obtained from the IAHSP patient compared to the other patients and controls. In addition, the hierarchical clustering analysis revealed that miR-451a was differentially expressed in fibroblasts and iPSCs, whereas miR-376a and miR-432 in neuronal cells. These results, together with the miRNA/mRNA target analysis, were indicative of a significant involvement of miR-451a in stem cell biology processes, and of miR-376a and miR-432 in the establishment of the neuronal phenotype. Our overall findings identified miR-376a, miR-432 and miR-451a as molecules involved in neuronal differentiation, and potentially in IAHSP pathogenesis, which could provide cues for future development of patient-specific miRNAbased therapeutic strategies for IAHSP or other motor neuron diseases.