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51.
Moreno JA Radford H Peretti D Steinert JR Verity N Martin MG Halliday M Morgan J Dinsdale D Ortori CA Barrett DA Tsaytler P Bertolotti A Willis AE Bushell M Mallucci GR 《Nature》2012,485(7399):507-511
The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2α-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2α-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2α-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2α-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation, increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders. 相似文献
52.
Maternal mRNA deadenylation and decay by the piRNA pathway in the early Drosophila embryo 总被引:2,自引:0,他引:2
Rouget C Papin C Boureux A Meunier AC Franco B Robine N Lai EC Pelisson A Simonelig M 《Nature》2010,467(7319):1128-1132
53.
Carla Eller Laura Heydmann Che C. Colpitts Eloi R. Verrier Catherine Schuster Thomas F. Baumert 《Cellular and molecular life sciences : CMLS》2018,75(21):3895-3905
Chronic hepatitis B, C and D virus (HBV, HCV and HDV) infections are a major cause of liver disease and cancer worldwide. Despite employing distinct replication strategies, the three viruses are exclusively hepatotropic, and therefore depend on hepatocyte-specific host factors. The sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes that mediates the transport of bile acids, plays a key role in HBV and HDV entry into hepatocytes. Recently, NTCP has been shown to modulate HCV infection of hepatocytes by regulating innate antiviral immune responses in the liver. Here, we review the current knowledge of the functional role and the molecular and cellular biology of NTCP in the life cycle of the three major hepatotropic viruses, highlight the impact of NTCP as an antiviral target and discuss future avenues of research. 相似文献
54.
A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep 总被引:38,自引:0,他引:38
Clop A Marcq F Takeda H Pirottin D Tordoir X Bibé B Bouix J Caiment F Elsen JM Eychenne F Larzul C Laville E Meish F Milenkovic D Tobin J Charlier C Georges M 《Nature genetics》2006,38(7):813-818
Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, we performed a whole-genome scan in a Romanov x Texel F2 population. We mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene. We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation. 相似文献
55.
Zanke BW Greenwood CM Rangrej J Kustra R Tenesa A Farrington SM Prendergast J Olschwang S Chiang T Crowdy E Ferretti V Laflamme P Sundararajan S Roumy S Olivier JF Robidoux F Sladek R Montpetit A Campbell P Bezieau S O'Shea AM Zogopoulos G Cotterchio M Newcomb P McLaughlin J Younghusband B Green R Green J Porteous ME Campbell H Blanche H Sahbatou M Tubacher E Bonaiti-Pellié C Buecher B Riboli E Kury S Chanock SJ Potter J Thomas G Gallinger S Hudson TJ Dunlop MG 《Nature genetics》2007,39(8):989-994
Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend; P = 1.41 x 10(-8)) and 1.14 (trend; P = 1.32 x 10(-5)), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07-1.26; P = 5.05 x 10(-4)). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23; P = 3.16 x 10(-11)). This locus has also been implicated in prostate cancer. 相似文献
56.
Le Chalony C Hoffschir F Gauthier LR Gross J Biard DS Boussin FD Pennaneach V 《Cellular and molecular life sciences : CMLS》2012,69(17):2933-2949
DNA ligase I (LigI) plays a central role in the joining of strand interruptions during replication and repair. In our current study, we provide evidence that DNA ligase III (LigIII) and XRCC1, which form a complex that functions in single-strand break repair, are required for the proliferation of mammalian LigI-depleted cells. We show from our data that in cells with either dysfunctional LigI activity or depleted of this enzyme, both LigIII and XRCC1 are retained on the chromatin and accumulate at replication foci. We also demonstrate that the LigI and LigIII proteins cooperate to inhibit sister chromatid exchanges but that only LigI prevents telomere sister fusions. Taken together, these results suggest that in cells with dysfunctional LigI, LigIII contributes to the ligation of replication intermediates but not to the prevention of telomeric instability. 相似文献
57.
Pansuriya TC van Eijk R d'Adamo P van Ruler MA Kuijjer ML Oosting J Cleton-Jansen AM van Oosterwijk JG Verbeke SL Meijer D van Wezel T Nord KH Sangiorgi L Toker B Liegl-Atzwanger B San-Julian M Sciot R Limaye N Kindblom LG Daugaard S Godfraind C Boon LM Vikkula M Kurek KC Szuhai K French PJ Bovée JV 《Nature genetics》2011,43(12):1256-1261
Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation. 相似文献
58.
Carosella ED Gregori S Rouas-Freiss N LeMaoult J Menier C Favier B 《Cellular and molecular life sciences : CMLS》2011,68(3):353-368
The non-classical HLA class I molecule HLA-G was initially shown to play a major role in feto–maternal tolerance. Since this
discovery, it has been established that HLA-G is a tolerogenic molecule which participates to the control of the immune response.
In this review, we summarize the recent advances on (1) the multiple structures of HLA-G, which are closely associated with
their role in the inhibition of NK cell cytotoxicity, (2) the factors that regulate the expression of HLA-G and its receptors,
(3) the mechanism of action of HLA-G at the immunological synapse and through trogocytosis, and (4) the generation of suppressive
cells through HLA-G. Moreover, we also review recent findings on the non-immunological functions of HLA-G in erythropoiesis
and angiogenesis. 相似文献
59.
Momozawa Y Mni M Nakamura K Coppieters W Almer S Amininejad L Cleynen I Colombel JF de Rijk P Dewit O Finkel Y Gassull MA Goossens D Laukens D Lémann M Libioulle C O'Morain C Reenaers C Rutgeerts P Tysk C Zelenika D Lathrop M Del-Favero J Hugot JP de Vos M Franchimont D Vermeire S Louis E Georges M 《Nature genetics》2011,43(1):43-47
Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ~20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease. 相似文献
60.
Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease 总被引:1,自引:0,他引:1
Fisher SA Tremelling M Anderson CA Gwilliam R Bumpstead S Prescott NJ Nimmo ER Massey D Berzuini C Johnson C Barrett JC Cummings FR Drummond H Lees CW Onnie CM Hanson CE Blaszczyk K Inouye M Ewels P Ravindrarajah R Keniry A Hunt S Carter M Watkins N Ouwehand W Lewis CM Cardon L;Wellcome Trust Case Control Consortium Lobo A Forbes A Sanderson J Jewell DP Mansfield JC Deloukas P Mathew CG Parkes M Satsangi J 《Nature genetics》2008,40(6):710-712
We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases. 相似文献