Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-ehdn.33
Marta Toczek, D. Zielonka, J. Marcinkowski, M. Isalan, R. Smolenski, M. Mielcarek
Huntington’s disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Metabolic remodelling is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. We established a lower enzymatic activity of enzymes involved in a degradation of cardiac nucleotides and an increased capacity for adenosine deamination. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction.
{"title":"A35 An altered metabolism of nucleotides leads to huntington’s disease related cardiomyopathy","authors":"Marta Toczek, D. Zielonka, J. Marcinkowski, M. Isalan, R. Smolenski, M. Mielcarek","doi":"10.1136/jnnp-2018-ehdn.33","DOIUrl":"https://doi.org/10.1136/jnnp-2018-ehdn.33","url":null,"abstract":"Huntington’s disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Metabolic remodelling is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. We established a lower enzymatic activity of enzymes involved in a degradation of cardiac nucleotides and an increased capacity for adenosine deamination. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction.","PeriodicalId":232122,"journal":{"name":"Pathogenic mechanisms","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133535743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/JNNP-2018-EHDN.10
L. Mégret, S. Nair, J. Aaronson, J. Rosinski, C. Néri
MicroRNA regulation could play important roles in modulating the dynamics of the Huntington’s disease (HD) process. The problems in question include those about the role of specific miRNAs in significantly modulating selective target genes and about the relations between these effects and the cellular context in which they operate. To address this question, we developed a data-driven approach based on network- and tree-based concepts for the unbiased and accurate characterization of miRNA regulation in the brain of HD knock-in mice (allelic series). This approach does not make use of prior knowledge on the relationships between miRNAs and their targets. Rather, it aims at predicting the miRNA-target pairs that are most strongly associated with the temporal dynamics of the HD process based on the in-depth analysis of age- and CAG repeat-dependent profiles of miRNA expression and target gene expression. Our results suggest that on a global level miRNA regulation may poorly explain gene deregulation in the cortex and striatum of HD knock-in mice. Nonetheless, our model retained a small number of miRNA-target pairs that in the striatum of HD knock-in mice are well anti-correlated in terms of change of expression level across age points and CAG-repeat lengths and that may be relevant to the modulation of neuronal activity in these HD mice.
{"title":"A10 Accurate data-driven approaches for modeling MIRNA regulation in the brain of huntington’s disease mice","authors":"L. Mégret, S. Nair, J. Aaronson, J. Rosinski, C. Néri","doi":"10.1136/JNNP-2018-EHDN.10","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.10","url":null,"abstract":"MicroRNA regulation could play important roles in modulating the dynamics of the Huntington’s disease (HD) process. The problems in question include those about the role of specific miRNAs in significantly modulating selective target genes and about the relations between these effects and the cellular context in which they operate. To address this question, we developed a data-driven approach based on network- and tree-based concepts for the unbiased and accurate characterization of miRNA regulation in the brain of HD knock-in mice (allelic series). This approach does not make use of prior knowledge on the relationships between miRNAs and their targets. Rather, it aims at predicting the miRNA-target pairs that are most strongly associated with the temporal dynamics of the HD process based on the in-depth analysis of age- and CAG repeat-dependent profiles of miRNA expression and target gene expression. Our results suggest that on a global level miRNA regulation may poorly explain gene deregulation in the cortex and striatum of HD knock-in mice. Nonetheless, our model retained a small number of miRNA-target pairs that in the striatum of HD knock-in mice are well anti-correlated in terms of change of expression level across age points and CAG-repeat lengths and that may be relevant to the modulation of neuronal activity in these HD mice.","PeriodicalId":232122,"journal":{"name":"Pathogenic mechanisms","volume":"69 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114256062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/JNNP-2018-EHDN.40
L. Abjean, Lucile Ben Haim, M. Sauvage, A. Hérard, C. Derbois, F. Petit, Pauline Gipstein, M. Guillermier, Mylène Gaudin, Suéva Bernier, N. Dufour, A. Bemelmans, J. Deleuze, P. Hantraye, G. Bonvento, R. Olaso, E. Brouillet, C. Escartin
Astrocytes are essential partners for neurons and their role in Huntington’s disease (HD) is emerging. In HD, astrocytes change and become reactive. Astrocyte reactivity is characterized by morphological changes but its functional impact is still unclear. To understand the roles of reactive astrocytes in HD, we have developed viral vectors that infect selectively astrocytes in vivo and either block or induce reactivity, through manipulation of the JAK2-STAT3 pathway. We used these vectors to modulate astrocyte reactivity in two complementary mouse models of HD [knock-in Hdh140 mice and lentivirus-mediated expression of a fragment of mutated Huntingtin (mHtt) in striatal neurons]. In these two models, we found that reactive astrocytes decrease the number and size of mHtt aggregates. How can reactive astrocytes reduce the aggregation of mHtt within neurons? We performed whole-genome transcriptomic analysis of acutely sorted reactive astrocytes to identify genes regulated by the JAK2-STAT3 pathway in astrocytes. We found an enrichment in genes linked to autophagy-lysosome and ubiquitin-proteasome systems, suggesting that reactive astrocytes have an enhanced capacity for protein degradation and could siphon mHtt away from neurons. Moreover, we identified several chaperones upregulated in reactive astrocytes. Chaperones prevent protein aggregation and can be released extracellularly. They could reduce mHtt aggregation within neurons themselves. Our data show that astrocytes develop a protective response in HD that involves bidirectional signaling with neurons to reduce mHtt aggregation. Reactive astrocytes are not only defective cells as usually reported, but also acquire enhanced capacities to promote mHtt clearance, which has strong therapeutic relevance for HD.
{"title":"A42 Reactive astrocytes promote proteostasis in huntington’s disease","authors":"L. Abjean, Lucile Ben Haim, M. Sauvage, A. Hérard, C. Derbois, F. Petit, Pauline Gipstein, M. Guillermier, Mylène Gaudin, Suéva Bernier, N. Dufour, A. Bemelmans, J. Deleuze, P. Hantraye, G. Bonvento, R. Olaso, E. Brouillet, C. Escartin","doi":"10.1136/JNNP-2018-EHDN.40","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.40","url":null,"abstract":"Astrocytes are essential partners for neurons and their role in Huntington’s disease (HD) is emerging. In HD, astrocytes change and become reactive. Astrocyte reactivity is characterized by morphological changes but its functional impact is still unclear. To understand the roles of reactive astrocytes in HD, we have developed viral vectors that infect selectively astrocytes in vivo and either block or induce reactivity, through manipulation of the JAK2-STAT3 pathway. We used these vectors to modulate astrocyte reactivity in two complementary mouse models of HD [knock-in Hdh140 mice and lentivirus-mediated expression of a fragment of mutated Huntingtin (mHtt) in striatal neurons]. In these two models, we found that reactive astrocytes decrease the number and size of mHtt aggregates. How can reactive astrocytes reduce the aggregation of mHtt within neurons? We performed whole-genome transcriptomic analysis of acutely sorted reactive astrocytes to identify genes regulated by the JAK2-STAT3 pathway in astrocytes. We found an enrichment in genes linked to autophagy-lysosome and ubiquitin-proteasome systems, suggesting that reactive astrocytes have an enhanced capacity for protein degradation and could siphon mHtt away from neurons. Moreover, we identified several chaperones upregulated in reactive astrocytes. Chaperones prevent protein aggregation and can be released extracellularly. They could reduce mHtt aggregation within neurons themselves. Our data show that astrocytes develop a protective response in HD that involves bidirectional signaling with neurons to reduce mHtt aggregation. Reactive astrocytes are not only defective cells as usually reported, but also acquire enhanced capacities to promote mHtt clearance, which has strong therapeutic relevance for HD.","PeriodicalId":232122,"journal":{"name":"Pathogenic mechanisms","volume":"38 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134201695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/JNNP-2018-EHDN.8
M. Figiel, Karolina Świtońska, Wojciech J. Szlachcic, Anna Philips, L. Handschuh, Michał Stelmaszczuk, Pawel Wojciechowski, M. Figlerowicz
HD is mainly a late-onset disorder, however, subtle symptoms in patients may occur years or even decades prior to diagnosis. Such changes at a molecular level may begin much earlier, even in stem cells. Here, we present a study defining the transcriptional profiles and early HD alterations in human HD-iPS cell lines. For the RNA sequencing analysis, we used three clonal HD lines with 71 CAG repeats, three juvenile HD clonal lines with 109 CAG repeats and control lines. HD-iPSC lines (71Q and 109Q) were compared with control lines where 82 significantly deregulated mRNAs were identified (30 downregulated and 52 upregulated). In addition 71Q lines were compared with control lines yielding 113 significantly deregulated mRNAs (33 downregulated and 80 upregulated). In the last group, in which 109Q lines were compared with control lines, 169 significantly deregulated mRNAs were identified (90 downregulated and 79 upregulated). The analysis revealed mRNAs which occurred in both HD lines (ex. OTOGL, TRIM69) but also many unique mRNAs, deregulated in 71Q (ex. PIWIL2, HIST1H3C) or HD109Q-iPSC lines (ex. TP53, CDKN1A). RNA sequencing was also focused on circular RNA (circRNA) profiling. Nearly 100 significantly deregulated circRNAs were identified, also showing many transcriptomic differences between 71Q and 109Q lines. The high-throughput RNA screening was followed by bioinformatics analyses, such as differential expression analysis and also over-representation and enrichment analyses which demonstrated several affected biological processes in iPSC. These processes were related with central nervous system development, disruption of the apoptosis pathway, enhanced DNA methylation and negative regulation of Wnt signaling pathway. RNA-seq and in silico analyses were then followed by experimental validation of the most deregulated and the most interesting mRNAs and digital droplet PCR for chosen circRNAs.
{"title":"A08 Early transcriptional changes in human HD-IPS cell lines revealed by RNASEQ","authors":"M. Figiel, Karolina Świtońska, Wojciech J. Szlachcic, Anna Philips, L. Handschuh, Michał Stelmaszczuk, Pawel Wojciechowski, M. Figlerowicz","doi":"10.1136/JNNP-2018-EHDN.8","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.8","url":null,"abstract":"HD is mainly a late-onset disorder, however, subtle symptoms in patients may occur years or even decades prior to diagnosis. Such changes at a molecular level may begin much earlier, even in stem cells. Here, we present a study defining the transcriptional profiles and early HD alterations in human HD-iPS cell lines. For the RNA sequencing analysis, we used three clonal HD lines with 71 CAG repeats, three juvenile HD clonal lines with 109 CAG repeats and control lines. HD-iPSC lines (71Q and 109Q) were compared with control lines where 82 significantly deregulated mRNAs were identified (30 downregulated and 52 upregulated). In addition 71Q lines were compared with control lines yielding 113 significantly deregulated mRNAs (33 downregulated and 80 upregulated). In the last group, in which 109Q lines were compared with control lines, 169 significantly deregulated mRNAs were identified (90 downregulated and 79 upregulated). The analysis revealed mRNAs which occurred in both HD lines (ex. OTOGL, TRIM69) but also many unique mRNAs, deregulated in 71Q (ex. PIWIL2, HIST1H3C) or HD109Q-iPSC lines (ex. TP53, CDKN1A). RNA sequencing was also focused on circular RNA (circRNA) profiling. Nearly 100 significantly deregulated circRNAs were identified, also showing many transcriptomic differences between 71Q and 109Q lines. The high-throughput RNA screening was followed by bioinformatics analyses, such as differential expression analysis and also over-representation and enrichment analyses which demonstrated several affected biological processes in iPSC. These processes were related with central nervous system development, disruption of the apoptosis pathway, enhanced DNA methylation and negative regulation of Wnt signaling pathway. RNA-seq and in silico analyses were then followed by experimental validation of the most deregulated and the most interesting mRNAs and digital droplet PCR for chosen circRNAs.","PeriodicalId":232122,"journal":{"name":"Pathogenic mechanisms","volume":"2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122121822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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