A: Pathogenic mechanisms最新文献

{"title":"A14 Retinal and striatal profiling of the r6/1 mouse model of huntington’s disease","authors":"L. M. Valor, Andrea Gallardo-Orihuela, F. Cano-Cano, L. Gómez-Jaramillo, Irati Hervás-Corpión, Francisco Martín-Loro, P. Villa, A. Arroba","doi":"10.1136/jnnp-2021-ehdn.13","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.13","url":null,"abstract":"","PeriodicalId":403341,"journal":{"name":"A: Pathogenic mechanisms","volume":"2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117158810","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}

{"title":"A12 Identification of the key role of white matter in the pathogenesis of huntington’s disease","authors":"Jean-Baptiste Pérot, Marina Célestine, M. Dhenain, S. Humbert, E. Brouillet, J. Flament","doi":"10.1136/jnnp-2021-ehdn.11","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.11","url":null,"abstract":"","PeriodicalId":403341,"journal":{"name":"A: Pathogenic mechanisms","volume":"27 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115027408","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}

{"title":"A16 Understanding the association between mitochondrial DNA copy number and telomere length in huntington’s disease patients","authors":"S. Venkatesh, P. Paul, B. Viswanath, R. Yadav, M. Varghese, S. Jain, M. Purushottam","doi":"10.1136/jnnp-2021-ehdn.15","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.15","url":null,"abstract":"Background Huntington’s disease (HD) is a progressive adult-onset neurodegenerative disorder, caused by pathogenic instability of CAG repeats in exon 1 of the HTT gene. Various subcellular structures and their function are known to be impaired, perhaps due to htt poly Q aggregates. Mitochondrial dysfunction and Telomeres shortening are among them. Aim To study the relative telomere length (RTL) and relative mitochondrial DNA (mtDNA) copy number in HD patients, as compared to controls; and the relationship between them. Methodology HD patients (N = 159) and healthy controls (N = 127) were studied. Relative mtDNA copy number was assessed by comparing the mitochondrial gene ND1 to a single copy nuclear gene PK1. And for the RTL, was computed by measuring telomere repeats, and the single-copy gene, 36B4 using specific primers. 2-ΔΔCt was calculated for each experiment as the measure of relative mtDNA copy number and RTL. Results The RTL was significantly lower in HD compared to controls (P = 0.042), whereas relative mtDNA copy number did not differ between HD and controls (P = 0.441). The relative mtDNA copy number showed significant positive association with RTL in controls (r = 0.197, P = 0.025), but not in HD patients (r = 0.057, P = 0.469). Conclusion Telomere length was attenuated in those with HD. The mitochondrial copy number did not show any difference. There was a significant association between RTL and relative mtDNA copy number in controls, but not in HD. Understanding the molecular mechanisms underlying telomere-mt DNA association is important.","PeriodicalId":403341,"journal":{"name":"A: Pathogenic mechanisms","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129768374","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}

{"title":"A21 Assessment of satellite progenitor cell differentiation in hd skeletal muscle in vitro","authors":"S. Hoque, K. Kucharz, M. Sjögren, A. Neueder, M. Orth, M. Björkqvist, Rana Soylu Kucharz","doi":"10.1136/jnnp-2021-ehdn.20","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.20","url":null,"abstract":"Background Intracellular calcium (Ca2+) transients regulate all aspects of cell function, including excitability, motility, exocytosis and gene expression. Abnormal Ca2+ signalling has been previously linked with Huntington’s disease (HD) neuropathology, however, how and to what extent it affects muscle tissue is unknown. Ghrelin is the gut-peptide hormone that induces intracellular Ca2+ mobilization by binding to ghrelin receptors in the skeletal muscle. Ghrelin may potentially modify HD muscle phenotype, thus be of relevance for HD treatment. Aim Our main goal is to establish a novel analytical platform to characterize intracellular Ca2+ dyshomeostasis and to assess the effect of ghrelin on Ca2+ dynamics in myofibers. Methods To assess intracellular Ca2+ transients in R6/2 mouse muscle cells and in clinical HD and control myoblasts in vitro, we isolate satellite cells from R6/2 and WT gastrocnemius muscle at postnatal days 7-9 and treat them with ghrelin for 3 days at the proliferation stage. Following 7 days of differentiation, we assess myofiber diameter, and gene expression by mRNA and protein levels of muscle-specific targets in response to ghrelin treatment. Results Compared to WT satellite cells, R6/2 satellite cells exhibit reduced myofiber diameter in vitro. MyoD (a protein which plays a crucial role in muscle differentiation) level is significantly decreased in R6/2 mice. Ghrelin treatment promotes myofiber formation, as ghrelin-treated satellite cells from R6/2 gastrocnemius muscle exhibit increased myofiber diameter and MyoD protein levels compared to the control group. Conclusion Our preliminary data suggest that treatment with ghrelin delays muscle atrophy in R6/2 mice at early stages of HD disease/phenotype. To understand its role in Ca2+ homeostasis, we will analyze intracellular Ca2+ signal patterns and correlate this with the morphological shape descriptors in satellite cells from both R6/2 mice and HD patients.","PeriodicalId":403341,"journal":{"name":"A: Pathogenic mechanisms","volume":"26 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121696554","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}

{"title":"A01 Investigating the effect of dna maintenance genes in drosophila melanogaster models of huntington’s disease","authors":"Freja M. Sadler, Thomas H. Massey, Gaynor A. Smith, L. Jones","doi":"10.1136/jnnp-2021-ehdn.1","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.1","url":null,"abstract":"","PeriodicalId":403341,"journal":{"name":"A: Pathogenic mechanisms","volume":"136 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116719520","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}

{"title":"A06 Tuning the stress response pathway to respond to polyq aggregation","authors":"C. L. Klaips, M. Gropp, M. Hipp, F. Hartl","doi":"10.1136/jnnp-2021-ehdn.5","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.5","url":null,"abstract":"","PeriodicalId":403341,"journal":{"name":"A: Pathogenic mechanisms","volume":"23 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125194919","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}

{"title":"A10 NAPDH oxidases (NOXs) exocytosis and its relevance in huntington’s disease (HD) pathology","authors":"L. Villegas, A. Nørremølle, K. Freude, F. Vilhardt","doi":"10.1136/jnnp-2021-ehdn.9","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.9","url":null,"abstract":"Huntington’s disease (HD) is an inherited, neurodegenerative disease (NDD) caused by a poly-glutamine expansion in the mutant Huntingtin (mHtt) protein. Neurodegeneration is a prominent feature in HD pathogenesis and most probably, neuron death itself is preceded by an initial neuronal dysfunction. NADPH oxidases (NOXs) belong to a family of transmembrane enzyme complexes producing Reactive Oxygen Species (ROS). NOXs are expressed in neurons in the CNS and play numerous roles in the regulation of neurodevelopment, neurite growth and synaptic plasticity. Even though impairment of these same processes has been shown in HD, very little is known about the role of NOXs in HD pathogenesis. Our group has shown a cell mechanism where NOXs are secreted into the extracellular space through exosomes. The exact biological function of the latter is still not fully elucidated, but it may have a role in the control of neurites growth and retraction. Indeed, specific NOX complexes are expressed differentially in neurons during differentiation, with opposing roles: NOX2 stimulates initial neurite outgrowth and NOX1 is essential for terminal neuronal differentiation. Huntingtin may regulate or impair NOX sorting into exosomes, since we have shown a differential exocytotic pattern when comparing healthy versus pathogenic HD cell models.","PeriodicalId":403341,"journal":{"name":"A: Pathogenic mechanisms","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132701970","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}

{"title":"A02 Striatal procedural memory-induced transcriptome and epigenome are severely impaired in huntington’s disease mice","authors":"R. Alcalá-Vida, C. Lotz, J. Séguin, B. Brulé, A. Awada, A. Bombardier, B. Cosquer, A. P. Vasconcelos, J. Cassel, A. Boutillier, K. Merienne","doi":"10.1136/jnnp-2021-ehdn.2","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.2","url":null,"abstract":"Background Huntington’s disease (HD) patients suffer from cognitive alterations involving striatal procedural learning and memory, preceding the onset of motor symptoms. However, underlying mechanisms remain poorly understood. In addition, specific transcriptional and epigenetic signatures characterize the striatum of HD patients and mouse models, but their relationship with cognitive impairment is unclear. Aims To develop a reliable behavioural task and assess striatal-dependent procedural learning and memory in HD mice and characterize transcriptional and epigenomic regulations participating in physiological and pathological cognitive processes. Methods We have adapted to mice a procedural task (the double-H maze) previously developed for rats, and tested control and R6/1 transgenic mice at early symptomatic stages. In parallel, we generated striatal transcriptomic (RNA-seq) and epigenomic (ChiP-seq) data using resting and behaving animals. Results R6/1 mice present an early impairment in striatal-dependent procedural learning and memory in the double-H task, preceding motor deficits, and accompanied by altered transcriptional regulation associated to learning and memory processes. Additionally, we profiled H3K27 acetylation (H3K27ac), H3K9 acetylation (H3K9ac) and RNA Polymerase II (RNAPII) using ChIP-seq on WT and R6/1 mouse striatum in basal state and during memory consolidation/recall. We observed a consistent depletion of H3K27ac, H3K9ac and RNAPII at striatal identity genes in R6/1 mice, strongly correlating with HD transcriptional alterations. Moreover, in WT mice striatum, H3K9ac was specifically modulated during memory process, and was notably implicated in the priming of myelin genes. Remarkably, this mechanism was deficient in R6/1 mice. Conclusions Our data highlight the role of epigenetic and transcriptional mechanisms in HD cognitive deficits, and provides a novel target, H3K9ac, as potential underlying mechanism.","PeriodicalId":403341,"journal":{"name":"A: Pathogenic mechanisms","volume":"241 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116144318","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}

{"title":"A17 Targeting mitophagy in huntington’s disease patients’ fibroblasts","authors":"I. Šonský, N. Volfová, M. Rodinová, P. Vodička, J. Klempír, H. Hansíková","doi":"10.1136/jnnp-2021-ehdn.16","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.16","url":null,"abstract":"","PeriodicalId":403341,"journal":{"name":"A: Pathogenic mechanisms","volume":"116 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124038538","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}

{"title":"A20 Assessment of muscle regeneration in the R6/2 mouse model of huntington’s disease","authors":"S. Hoque, Rana Soylu Kucharz, V. Allamand, M. Sjögren, K. Gawlik, Naomi Franke, J. Lundin, Å. Petersén, M. Durbeej, M. Björkqvist","doi":"10.1136/jnnp-2021-ehdn.19","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.19","url":null,"abstract":"Background Skeletal muscle atrophy is one of the hallmarks of Huntington’s disease (HD), and it correlates with inflammation, mitochondrial dysfunction, and altered energy metabolism. Although improvement in muscle wasting has been shown to slow disease progression and increase life span in animal models, the precise mechanism of overall muscle wasting is not well studied. Aim Using an acute injury model, we aimed to investigate the effects of mutant HTT expression on satellite cell regeneration capacity in the R6/2 mouse model. Methods We used adult and neonatal R6/2 mice and their WT littermates. A chemical injury model was employed using cardiotoxin (CTX) in the tibialis anterior muscle. To assess tissue remodeling, we performed immunohistochemistry using laminin to stain basement membrane and embryonic myosin heavy chain (eMHC) as an indicator of muscle regeneration at 4 weeks and 1 week of post-CTX injection, respectively. Results Body weight and fiber diameter were significantly reduced in both adult and neonatal R6/2 mice compared to WT littermates. At four weeks post-injection, fiber diameter was the same between saline and CTX injected group in WT mice. Yet, fiber diameter was increased in the R6/2 CTX compared to the R6/2 saline group. We found a trend towards increased eMHC positive cells in R6/2 compared to the WT littermates at 1-week post-injection. Conclusion R6/2 skeletal muscle has the ability to regenerate new fibers following an acute injury, and the regeneration process was not profoundly affected by mutant huntingtin expression. We will further investigate HD satellite cell proliferation capacity (i.e., Pax7 positive cells) and inflammatory response (i.e., CD68, CD11b) in response to acute muscle injury.","PeriodicalId":403341,"journal":{"name":"A: Pathogenic mechanisms","volume":"26 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116320670","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}