A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy
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PROVIDER: PRJNA701665 | ENA |
REPOSITORIES: ENA
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Project description:A juvenile form of paroxysmal dyskinesia segregated in the Markiesje dog breed. Affected pups exhibited clinical signs of a severe tetraparesis, dystonia, cramping and falling over when trying to walk. In most cases the presentation deteriorated within weeks and elective euthanasia was performed. Pedigree analysis indicated autosomal recessive inheritance. Genome-wide association and homozygosity mapping of 5 affected dogs from 3 litters identified the associated locus on chromosome 31 in the region of SOD1. The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon. None of the other analyzed dogs of the breed was homozygous for the mutation, indicating full penetrance of the genetic defect. Mutations in SOD1 are known to cause recessive degenerative myelopathy in middle-aged dogs with low penetrance and dominant amyotrophic lateral sclerosis in humans with variable age of onset. Our findings are similar to recent observations in human patients that a loss of function mutation in SOD1 leads to a juvenile neurologic disease distinct from amyotrophic lateral sclerosis.
2021-03-12 | GSE166712 | GEO
Project description:A juvenile form of paroxysmal dyskinesia segregated in the Markiesje dog breed. Affected pups exhibited clinical signs of a severe tetraparesis, dystonia, cramping and falling over when trying to walk. In most cases, the presentation deteriorated within weeks and elective euthanasia was performed. Pedigree analysis indicated autosomal recessive inheritance. Genome-wide association and homozygosity mapping of 5 affected dogs from 3 litters identified the associated locus on chromosome 31 in the region of SOD1. The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon. None of the other analyzed dogs of the breed was homozygous for the mutation, indicating full penetrance of the genetic defect. Mutations in SOD1 are known to cause recessive degenerative myelopathy in middle-aged dogs with low penetrance and dominant amyotrophic lateral sclerosis in humans with variable age of onset. Our findings are similar to recent observations in human patients that a loss of function mutation in SOD1 leads to a juvenile neurologic disease distinct from amyotrophic lateral sclerosis.
| S-EPMC8519843 | biostudies-literature
Project description:Dyskinesias are characterized by abnormal repetitive involuntary movements due to dysfunctional neuronal activity. Although levodopa-induced dyskinesia, characterized by tic-like abnormal involuntary movements, has no clinical treatment for Parkinson’s disease patients, animal studies indicate that Riluzole, which interferes with glutamatergic neurotransmission, can improve the phenotype. The rat model of levodopa-induced dyskinesia is a unilateral lesion with 6-hydroxydopamine in the medial forebrain bundle, followed by the repeated administration of levodopa. The molecular pathomechanism of levodopa-induced dyskinesia is still not deciphered, however implication of epigenetic mechanisms was suggested. In this study, we investigated the striatum for DNA methylation alterations under chronic levodopa treatment with or without co-treatment with Riluzole. Our data show that the lesioned and contralateral striata have nearly identical DNA methylation profiles. Chronic levodopa and levodopa+Riluzole treatments led to DNA methylation loss, particularly outside of promoters, in gene bodies and CpG poor regions. We observed that several genes involved in the levodopa-induced dyskinesia underwent methylation changes. Furthermore, the Riluzole co-treatment, which improved the phenotype, pinpointed specific methylation targets, with more than 20% methylation difference relative to levodopa treatment alone. These findings indicate potential new druggable targets for levodopa-induced dyskinesia.
2021-06-03 | GSE176004 | GEO
Project description:In our original grant we proposed to use the NR3B-null mouse model to study the role of NR3B subunit in motor neuron function. We have now successfully generated NR3B null mice. Interestingly, NR3B-null mice invariably die at age P4-P8. Our preliminary examination indicates that the motor strength of these mice is severely impaired prior to death. As we continue to explore the cause of death in NR3B null mice, we propose to conduct gene profiling experiments to search for transcription changes in the brain related to ablation of the NR3B gene. We have used the facility provided by the NINDS/NIMH Microarray Consortium to identify genes that show abnormal expression patterns in these mice. We would like to compare these changes with that opccured in SOD1 mice, a mouse model of motor neuron diseases. Analysis of these genes will help to identify changes in networks and pathways that may cause the death of NR3B-null mice. These studies will further help to elucidate the functional role of NR3B in motor neurons. We will compare samples from motor neurons of wild type and SOD1 mice to identify genes that show abnormal expression patterns, which may be implicated in the death of SOD1 mice and shared with the same changes in NR3B-null mice. We hypothesize that genes with their transcription level changing significantly in SOD1 mutant mice will be associated with the molecular mechanism underlying the death of motor neurons. We like to compare motor neuron and spinal cord smaples from SOD1 mice at the age prior to the disease onset. Total RNA from total 9 samples will be purified, each from ~200 motor neurons obtained by Laser Capture Microdissection and the total spinal cord. Extracted RNAs will be subjected to one or two rounds of amplification and the obtained cRNA will be biotinylated. The purified cRNA will be sent to the NINDS/NIMH Microarray Consortium be used to hybridize the GeneChip Mouse Genome 430 2.0 Array. The hybridization, scanning, and initial data analysis of these GeneChips will be conducted by the Consortium staff. We will analyze the collected data further after data collection. We will first identify genes that show significant changes between wild-type and SOD1 mice and then compare that with the result from NR3B null mice.
2008-06-13 | E-GEOD-5038 | biostudies-arrayexpress
Project description:Missense mutations in the gene for the ubiquitously expressed superoxide dismutase-1 (SOD1) are one of the causes of familial amyotrophic lateral sclerosis (ALS), the most common adult onset motor neuron disease in humans killing selectively large motor neurons. Mice and rats overexpressing mutant SOD1 develop an adult onset neurodegenerative disease with hindlimb-paralysis and subsequent death similar to the human condition. In order to analyze the effects of mutant SOD1 expression onto the most affected cell-type in ALS, a small subpopulation of spinal cord cells, we propose to use laser microdissection to isolate mouse lumbar motor neurons and to assess the changes onto the mRNA expression profile using Affymetrix GeneChips compared to control animals. While two studies applying a genomic approach on the ALS mouse models used the entire spinal cord, contributions of changes to motor neurons were masked by the inflammatory effects of mutant SOD1 and the much larger population of non-motor neuronal cells. What is therefore needed is a cell-type specific expression profile that could reveal dysregulations in the transcriptome of the affected motor neurons. In order to find and analyze disease relevant gene expression profile changes in the mutant vs. the wildtype overexpressing SOD1 mice, we propose to use two different mutant SOD1 lines. Both lines develop the same ALS-like motor neuron disease, however, line 1 (with a G37R mutation) retains the full activity of the SOD1 enzyme while line 2 (with a G85R mutation) has almost no SOD1 enzymatic activity. We believe that by using these two most extreme variants of ALS-inducing mutant SOD1 forms, candidate genes that will be similarly dysregulated in both mutant lines will have great potential to be a disease relevant hit. We will collect from both mutant SOD1 mouse lines lumbar motor neurons from three presymptomatic timepoints, equally distributed during their adult life and before obvious hindlimb-weakness or paralysis signs and compare them to two control lines, negative littermates and wildtype SOD1 overexpressing mice. Furthermore, to determine if their are already mutant SOD1-induced changes since the formation of the affected cells, we will also isolate embryonic spinal cord motor neurons and compare them between mutant SOD1 and wildtype SOD1 overexpressing animals. Both, mice deleted in wildtype SOD1 and mice overexpressing mutant human SOD1 clearly established that the toxic property of mutant SOD1 is based upon a gain-of-toxic function phenomenon rather than a loss-of-function effect, since the SOD1 knock-out mice are overall normal. Furthermore, mice overexpressing wildtype SOD1 are healthy and serve as ideal control animals. Therefore, one of the most important question in ALS is to determine what slowly acting mechanism, or build-up of toxic products is responsible for ultimately killing more than 50-70% of the large lumbar spinal cord motor neurons. We hypothezise that the toxic property of mutant SOD1 must already induce changes onto the transcriptome of the most at-risk cell-type, the large lumbar spinal cord motor neuron, very early on in the presymptomatic phase of the disease course, when the animal is still without any paralysis signs and moving normally around the cage. We will choose 3 timepoints before phenotypic disease-onset that is at 22 weeks for the SOD1G37R line (L42) and at 11 months for the SOD1G85R line (L148). The timepoints are 8, 15 and 18 weeks for SOD1G37R line and 4, 7.5 and 9 months for the SOD1G85R line all compared to age-matched control animals (wildtype SOD1 overexpressing mice (L76) for the SOD1G37R line (high mutant SOD1 levels) and negative littermates for the SOD1G85R line (low mutant SOD1 levels)). Using the Leica lasermicrodissection system on fresh frozen spinal cord sections, we process a single spinal cord sample in 3 days resulting in approximately 4000 ventral horn motor neurons collected from 150 consecutive 20 um sections of the most affected lumbar spinal cord region (L4-L6). To visualize the motor neurons, we have established a fast Nissel-staining protocol that is optimized for speed to preserve the integrity of the RNA. Before lasermicrodissection slides containing 5 spinal cord sections are dessicated for 1 hour and samples are collected directly into RNA-preserving lysis-buffer. Using Stratagene's NanoPrep RNA-extraction columns a yield of around 150 ng of total RNA was obtained (Ribogreen-quantification), that is enough for both the 2-round linear RNA amplification and for future candidate confirmation studies using real-time PCR analysis. We are using the Affymetrix Two-Cycle 3'-Amplification Kit, starting with 100 ng of total RNA and will hybridize on Affymetrix Mouse 430 2.0 GeneChips. Embryonic motor neurons are isolated from e14 mutant SOD1G93A overexpressing rat embryos and compared to wildtype SOD1 overexpressing embryos using a metrazimide gradient followed by a p75-antibody purification in combination with magnetic beads. Cells from one litter of embryos were directly collected into lysis-buffer, yielding at least 200-500 ng of total RNA, enough for one Rat 230 2.0 GeneChip (2-round amplification using 100 ng total RNA). Keywords: time-course
2007-04-11 | GSE7493 | GEO
Project description:Degenerative myelopathy (DM) is a canine disease very similar to amyotrophic lateral sclerosis (ALS) in humans. We previously showed that DM is a promising model for ALS, as genome-wide association identified a mutation in SOD1, a known ALS gene. In this study, we identify a modifier gene, SP110, which strongly affects overall disease risk and age-of-onset in Pembroke Welsh corgis at risk of DM. Dissecting the complex genetics of this disease in a model organism may lead to new insights about risk and progression in both canine and human patients. 15 DM-affected and 31 unaffected PWC homozygous for SOD1 mutation genotyped using the Illumina CanineHD array (~170,000 SNPs genomewide)
2016-06-01 | E-GEOD-80735 | biostudies-arrayexpress
Project description:Degenerative myelopathy (DM) is a canine disease very similar to amyotrophic lateral sclerosis (ALS) in humans. We previously showed that DM is a promising model for ALS, as genome-wide association identified a mutation in SOD1, a known ALS gene. In this study, we identify a modifier gene, SP110, which strongly affects overall disease risk and age-of-onset in Pembroke Welsh corgis at risk of DM. Dissecting the complex genetics of this disease in a model organism may lead to new insights about risk and progression in both canine and human patients. 15 DM-affected and 10 unaffected Boxers homozygous for SOD1 mutation genotyped using the Illumina CanineHD array (~170,000 SNPs genomewide)
2016-06-01 | E-GEOD-80315 | biostudies-arrayexpress
Project description:Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the selective loss of motor neurons. Mutations in Cu/Zn superoxide dismutase (SOD1) are the second most common cause of ALS and it is now well accepted that they result in a gain of toxicity due to protein misfolding. We previously demonstrated in the SOD1G93A rat model that misfolded SOD1 exists as distinct conformers and deposits on mitochondrial subpopulations. Here, using SOD1G93A rats coupled with conformation-restricted antibodies for misfolded SOD1 (AMF7-63 and B8H10), we identified the interactomes of the mitochondrial pools of misfolded SOD1. This strategy identified binding partners that uniquely interacted with either AMF7-63- or B8H10-reactive SOD1 conformers as well as a high proportion of interactors common to both conformers. Of this latter set, we identified the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) and determined that exposure of the SOD1 functional loops facilitates this interaction. However, this conformational criterion is not universally fulfilled by all SOD1 mutants and differentiates TRAF6-interacting from non-interacting SOD1 mutants. Functionally, TRAF6 stimulates mutant SOD1 polyubiquitination and aggregation. While TRAF6 E3 ubiquitin ligase activity is required for the former, it is dispensable for the latter, indicating that the polyubiquitination and aggregation of mutant SOD1 mediated by TRAF6 are independent events. We propose that misfolded SOD1 binding to TRAF6 may be relevant to ALS disease.
2020-02-24 | PXD015279 | Pride
Project description:mRNA expression in the spinal cords of the G93A-SOD1 familial ALS transgenic mouse model was compared to that in nontransgenic (Normal mouse) and transgenic mice expressing wild-type (WT)SOD1. Gene Ontology (GO)analysis was used to characterize differences in expression between G93A-SOD1 mouse and nontransgenic mouse spinal cord. Changes in multiple GO categories were found. Many of these were associated with subsystems involving cell-cell communication and intracellular signal transduction. Expression profiles of mice expressing WT-SOD1 did not differ from nontransgenic mice. In contrast, protein profiling using proteomics technology indicated changes in mitochondrial protein expression in the G93A-SOD1 mouse spinal cord that were not found in the mRNA expression analysis. Keywords: Disease state analysis, time course, transgenic mice
2006-03-09 | GSE4390 | GEO
Project description:Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases.
2023-11-30 | GSE196843 | GEO