Mitochondrial DNA allelic substitutions in Parkinson’s disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE113704 | GEO | 2019/05/21
REPOSITORIES: GEO
Similar Datasets
Project description:Mitochondrial DNA allelic substitutions in Parkinson’s disease
| PRJNA453701 | ENA
Project description:Many observations suggest that mutations of mtDNA could be responsible of the neurodegenerative changes associated with AD. We examined the signal intensity of the four alleles for each mtDNA nucleotide position (np) in whole blood of AD patients and age-matched controls utilizing a resequencing array, the MitoChip v2.0, and identified 275 statistically different nps which all, with the exception of one, showed an increased contribution of non-reference alleles for AD patients. PCA and cluster analysis showed that 5 of these nps, characterized by low-level heteroplasmy, could discriminate AD from control subjects with 80% of cases correctly classified.
2014-03-11 | GSE49160 | GEO
Project description:Many observations suggest that mutations of mtDNA could be responsible of the neurodegenerative changes associated with AD. We examined the signal intensity of the four alleles for each mtDNA nucleotide position (np) in whole blood of AD patients and age-matched controls utilizing a resequencing array, the MitoChip v2.0, and identified 275 statistically different nps which all, with the exception of one, showed an increased contribution of non-reference alleles for AD patients. PCA and cluster analysis showed that 5 of these nps, characterized by low-level heteroplasmy, could discriminate AD from control subjects with 80% of cases correctly classified. This study included a total of 18 AD patients and 18 age-matched controls. Data acquisition was performed using the Affymetrix Genechip Command Console (AGCC) software and data analysis was carried out with GSEQ 4.1.
2014-03-11 | E-GEOD-49160 | biostudies-arrayexpress
Project description:Introduction: Parkinson's disease (PD), typically developing between the ages of 55 and 65 years, is a common neurodegenerative disorder caused by a progressive loss of dopaminergic neurons due to the accumulation of α-synuclein in the substantia nigra. Mitochondria are known to play a key role in cell respiratory function and bioenergetic. Indeed, mitochondrial dysfunction causes an insufficient energy production required to satisfy the needs of several organs, especially the nervous system. Material and methods: The present study explored the mRNA expression of mitochondrial DNA (mtDNA) encoded respiratory chain (RC) subunits in PD patients by using the next generation sequencing analysis (NGS) and the quantitative real-time PCR (qRT-PCR) assay for the confirmation of the NGS results. Results: All tested mitochondrial RC subunits was significantly over-expressed in subjects with PD compared to normal controls . In qRT-PCR the mean expression of all mitochondrial subunits had an expression level of at least 7 times compared to controls. Conclusion: The over-expression of mitochondrial subunits in PD subjects might be secondary to a degeneration-related alteration of the mitochondrial structure or dynamics or to the occurrence of a compensatory mechanism. The study of specific mRNA by peripheral blood mononuclear cells (PBMCs) may provide a better diagnostic frame to early detect PD cases.
2022-01-01 | E-MTAB-9950 | biostudies-arrayexpress
Project description:This study aimed to evaluate single nucleotide substitutions in mtDNA and analyze their correlation with inflammatory biomarkers in elderly COVID-19 patients. A total of 30 COVID-19 patients and 33 older adult controls (aged over 65 years) were enrolled. mtDNA was extracted from buffy coat samples and sequenced using a chip-based resequencing system (Affymetrix MitoChip v2.0) which detects both homoplasmic and heteroplasmic mtDNA mutations, and allows the assessment of low-level heteroplasmy. Serum concentration of IL-6, IFN-α, TNF-α and IL-10 were determined in patients by a high-sensitivity immunoassay. We found a higher burden of total heteroplasmic mutation in COVID-19 patients compared to controls with a selective increment in ND1 and COIII genes. Low-level heteroplasmy was significantly elevated in COVID-19 patients, especially in genes of the respiratory complex I. Both heteroplasmic mutation burden and low-level heteroplasmy were associated with increased levels of IL-6, TNF-α, and IFN-α.
2024-01-23 | GSE235626 | GEO
Project description:Individual variation in complex traits results from allelic variants of multiple segregating genes, which are expressed as coregulated ensembles that are modulated by the environment. Coregulated transcriptional networks around focal genes, defined as their ‘transcriptional niches’, are sensitive to genetic and environmental perturbations. Understanding how single base pair substitutions affect this complex genotype-phenotype relationship by perturbing transcriptional niches is possible in Drosophila, which allows precise control of both the genetic background and the environment. We used a two-step CRISPR-Cas9 mediated gene deletion and reinsertion strategy to generate in a common genetic background five single nucleotide substitutions in the D. melanogaster Obp56h gene that correspond to naturally occurring allelic variants. Changes in single base pairs give rise to differential, sexually dimorphic effects on a plethora of fitness traits, including viability, sex ratio, feeding behavior, starvation resistance, recovery from a chill-induced coma, response to heat shock, activity, and sleep traits. These pleiotropic effects are accompanied by sexually dimorphic shifts in the transcriptional niche of Obp56h. Pairwise comparisons between the lines show common coregulated genes along with varying numbers of transcripts unique to one or few Obp56h alleles. Gene ontology enrichment analyses indicate that fundamental cellular processes for each sex underlie the phenotypic pleiotropy revealed by the Obp56h allelic series. Furthermore, different Obp56h alleles in a common genetic background give rise to allele-specific, sexually dimorphic microenvironmental variation. The reverse genetic engineering strategy, illustrated here, can be generally applied to other genes to dissect variation in the genotype-phenotype relationship at single base pair resolution.
2022-03-10 | GSE178635 | GEO
Project description:Mutant KRAS (mut-KRAS) is present in 30% of all human cancers and plays a critical role in cancer cell growth and resistance to therapy. There is evidence from colon cancer that mut-KRAS is a poor prognostic factor and negative predictor of patient response to molecularly targeted therapy. However, evidence for such a relationship in non small cell lung cancer (NSCLC) is conflicting. KRAS mutations are primarily found at codons 12 and 13, where different base changes lead to alternate amino acid substitutions that lock the protein in an active state. The patterns of mut-KRas amino acid substitutions in colon cancer and NSCLC are quite different, with aspartate (D) predominating in colon cancer (50%) and cysteine (C) in NSCLC (47%). Through an analysis of a recently completed biopsy biomarker-driven, molecularly targeted multi-arm trial of 215 evaluable patients with refractory NSCLC we show that mut-KRas-G12C/V but not total mut-KRAS predicts progression free survival for the overall group, and for the sorafenib and vandetanib treatment arms. Transcriptome microarray data shows differential expression of cell cycle genes between mut-KRas-G12C/V and G12D patient tumors. A panel of NSCLC cell lines with known mut-KRas amino acid substitutions was used to identify pathways activated by the different mut-KRas, showing that mut-KRas-G12D activates both PI-3-K and MEK signaling, while mut-KRas G12C does not, and alternatively activates RAL signaling. This finding was confirmed using immortalized human bronchial epithelial cells stably transfected with wt-KRAS and different forms of mut-KRAS. Molecular modeling studies show that the different conformation imposed by mut-KRas-G12C could lead to altered association with downstream signaling transducers compared to wild type and mut-KRas-G12D. The significance of the findings for developing mut-KRAS therapies is profound, since it suggests that not all mut-KRas amino acid substitutions signal to effectors in a similar way, and may require different therapeutic interventions. Gene expression profiles were measured in 22 core biopsies from patients with refractory non-small cell lung cancer included in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE). All tumors were KRAS mutants, but with different patterns of amino acid substitutions. Supervised analysis of transcriptome profiling was performed to compare cysteine or valine KRAS mutants with other KRAS mutants.
2012-01-01 | E-GEOD-27389 | biostudies-arrayexpress
Project description:Parkinson’s disease (PD) is the most common movement disorder in the aging population, with an estimated prevalence of 1% of people above 60 years old. More recently, PD risk genes, have been found to be regulated by the small non-coding RNAs, (microRNAs or miRNAs), and, as such, may contribute to PD development through a direct regulation on the mitochondrial and immune pathways. Many of these are influenced by epigenetic mechanisms, among which ones mediated by, miRNAs, that regulate gene expression at a post transcriptional level by binding to their 3′ un-translated region (3′ UTR) of target messenger RNAs (mRNAs) inducing mRNA degradation and translational repression. This study aimed to identify and characterize miRNA to evaluate their possible deregulation in PD patients compared to CRTL. In addition, we investigated how specific miRNAs are able to target genes and, thus, to modulate their functions in PD patient. Small RNA expression profiling was performed by next-generation sequencing in PD patients and CTRL after filtered out low-quality reads and trimming the adaptors. The obtained high-quality reads were aligned against the human genome reference.
2023-09-01 | E-MTAB-12087 | biostudies-arrayexpress
Project description:We performed a Massively Parallel Reporter Assay (MPRA) to screen >30,000 human-specific substitutions in ChIP-seq-identified Human Gain Enhancers (HGEs) and Human Accelerated Regions (HARs), highly conserved non-coding regions that show accelerated sequence evolution in humans. After comparing human and chimpanzee reference alleles, we used a second MPRA to deconvolute individual substitutions within differentially active enhancers from substitutions in the same fragment and from other variants (human segregating variants or chimpanzee-specific variants) to isolate their specific effects on enhancer activity.
2019-11-26 | GSE140983 | GEO
Project description:We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested.
2021-10-12 | E-MTAB-11029 | biostudies-arrayexpress