Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy.
P40 is the protein encoded by the first open reading frame (ORF1) of the human LINE‐1 (L1Hs) retrotransposon; it is 338 amino acids long, has a leucine zipper motif and has been found in human teratocarcinoma cell lines and some tumor cells. In this report, we describe properties of p40 in the human teratocarcinoma cell lines NTera2D1 and 2102Ep. The results indicate that: (i) most of p40 occurs in large multimeric cytoplasmic complexes, (ii) L1Hs RNA is associated with the p40 complexes, (iii) the complexes are dissociated by ribonuclease and (iv) p40 is a novel RNA‐binding protein. Cross‐linking experiments with full‐length and truncated p40 produced in Escherichia coli also showed that: (i) p40 itself can form a multimeric complex larger than 250 kDa, (ii) the leucine zipper motif and the region conserved among the predicted ORF1 polypeptides of mammalian LINE‐1s participate in complex formation and (iii) the amino terminal region is important for the stability of complex formation. Analysis of the amino acid sequence of p40 suggests that long segments of the molecule can assume an alpha‐helical configuration including the leucine zipper and the conserved region. The evidence presented here suggests that the p40 complex is a ribonucleoprotein complex containing L1Hs RNA(s) and that protein‐protein interactions in which alpha‐helix structures participate, for example coiled‐coils, may occur in the complex.
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. Foxp3+ regulatory T (Treg) cells are reduced in frequency and dysfunctional in patients with MS, but the underlying mechanisms of this deficiency are unclear. Here, we show that induction of human IFN-γ−IL-17A−Foxp3+CD4+ T cells is inhibited in the presence of circulating exosomes from patients with MS. The exosomal miRNA profile of patients with MS differs from that of healthy controls, and let-7i, which is markedly increased in patients with MS, suppresses induction of Treg cells by targeting insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1). Consistently, the expression of IGF1R and TGFBR1 on circulating naive CD4+ T cells is reduced in patients with MS. Thus, our study shows that exosomal let-7i regulates MS pathogenesis by blocking the IGF1R/TGFBR1 pathway.
Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2. However, in mice lacking NR4A2 in T cells, a late-onset disease is still inducible, despite a great reduction in acute inflammation. We here reveal that development of this late onset disease depends on cytotoxic T-cell-like CD4+ T cells expressing the T-box transcription factor Eomesodermin (Eomes). T-cell-specific deletion of the Eomes gene remarkably ameliorates the late-onset EAE. Strikingly, similar Eomes+ CD4+ T cells are increased in the peripheral blood and cerebrospinal fluid from patients in a progressive state of multiple sclerosis. Collective data indicate an involvement of granzyme B and protease-activated receptor-1 in the neuroinflammation mediated by Eomes+ CD4+ T cells.
several kinds of tumor cells (Leibold et al., 1990; Institutes of Health, Bethesda, MD 20892 and 2 Carnegie Institution of Bratthauer and Fanning, 1992). ORF2 predicts an Washington, 1530 P Street NW, Washington, DC 20005, USA~1 49 kDa protein with which are associated two activities, 3 Corresponding author DNA endonuclease (Feng et al., 1996) and reverse transcriptase (Dombroski et al., 1991; Mathias et al., 1991; Previous experiments using human teratocarcinoma Moran et al., 1996; Sassaman et al., 1997 et al., 1996). L1Hs RNA(s), the p40 RNP complex. We have nowPreviously we showed that p40 occurs in a cytoplasmic investigated the interaction between partially purified ribonucleoprotein complex (called the p40 RNP complex) p40 and L1Hs RNA in vitro using an RNA binding in human teratocarcinoma cells growing in culture (Hohjoh assay dependent on co-immunoprecipitation of p40 and and Singer, 1996). This p40 RNP complex contains L1Hs bound RNA. These experiments identified two p40RNA and the RNA appears to be directly bound to p40. binding sites on the full-length sense strand L1HsThe p40 RNP complex is large; it elutes in the void RNA. Both sites are in the second ORF of the 6000 nt volume of a Sephacryl S-400 column and is thus likely RNA: site A between residues 1999 and 2039 and site to be Ͼ700 kDa. When the p40 RNP complex is treated B between residues 4839 and 4875. The two RNA with high salt, the RNA is released and p40 can be segments share homologous regions. Experiments recovered as multimers in the size range 200 kDa; treatinvolving UV cross-linking followed by immunoment of the p40 RNP complex with various ribonucleases precipitation indicate that p40 in the in vitro complex yields similar multimers (Hohjoh and Singer, 1997). No is directly associated with L1Hs RNA, as it is in the components of the complexes other than L1Hs RNA p40 RNP complex found in teratocarcinoma cells. Results Preparation of p40
Recent studies showed that small interfering RNAs (siRNAs) and Piwi-interacting RNA (piRNA) in mammalian germ cells play important roles in retrotransposon silencing and gametogenesis. However, subsequent contribution of those small RNAs to early mammalian development remains poorly understood. We investigated the expression profiles of small RNAs in mouse metaphase II oocytes, 8–16-cell stage embryos, blastocysts and the pluripotent inner cell mass (ICM) using high-throughput pyrosequencing. Here, we show that during pre-implantation development a major small RNA class changes from retrotransposon-derived small RNAs containing siRNAs and piRNAs to zygotically synthesized microRNAs (miRNAs). Some siRNAs and piRNAs are transiently upregulated and directed against specific retrotransposon classes. We also identified miRNAs expression profiles characteristic of the ICM and trophectoderm (TE) cells. Taken together, our current study reveals a major reprogramming of functional small RNAs during early mouse development from oocyte to blastocyst.
ARX (the aristaless-related homeobox gene) is a transcription factor that participates in the development of GABAergic and cholinergic neurons in the forebrain. Many ARX mutations have been identified in X-linked lissencephaly and mental retardation with epilepsy, and thus ARX is considered to be a causal gene for the two syndromes although the neurobiological functions of each mutation remain unclear. We attempted to elucidate the causal relationships between individual ARX mutations and disease phenotypes by generating a series of mutant mice. We generated three types of mice with knocked-in ARX mutations associated with X-linked lissencephaly (P353R) and mental retardation [P353L and 333ins(GCG)7]. Mice with the P355R mutation (equivalent to the human 353 position) that died after birth were significantly different in Arx transcript/protein amounts, GABAergic and cholinergic neuronal development, brain morphology and lifespan from mice with P355L and 330ins(GCG)7 but considerably similar to Arx-deficient mice with truncated ARX mutation in lissencephaly. Mice with the 330ins(GCG)7 mutation showed severe seizures and impaired learning performance, whereas mice with the P355L mutation exhibited mild seizures and only slightly impaired learning performance. Both types of mutant mice exhibited the mutation-specific lesser presence of GABAergic and cholinergic neurons in the striatum, medial septum and ventral forebrain nuclei when compared with wild-type mice. Present findings that reveal a causal relationship between ARX mutations and the pleiotropic phenotype in mice, suggest that the ARX-related syndrome, including lissencephaly or mental retardation, is caused by only the concerned ARX mutations without the involvement of other genetic factors.
RNA interference (RNAi) is a powerful tool for suppressing the expression of a gene of interest, in which 21^25 nucleotide short interfering RNA (siRNA) duplexes homologous to the silenced gene function as sequence-speci¢c RNAi mediators. The present study shows that newly designed siRNA duplexes, 'fork-siRNA duplexes', whose sense-stranded siRNA elements carry one to four nucleotide mismatches at the 3P P-ends against the antisense-stranded siRNA elements, can enhance RNAi activity over conventional siRNA duplexes in cultured mammalian cells.
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