Gene expression changes across multiple regions of the Parkinson’s disease brain
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE28894 | GEO | 2011/07/22
SECONDARY ACCESSION(S): PRJNA140647
REPOSITORIES: GEO
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Project description:We have used microarrays to analyze gene expression in Parkinson’s disease (PD). We used four different brain regions, including two that are relatively affected in PD (striatum and cortex) and two that are relatively spared (cerebellum and medulla). We show that while differences between brain regions are strong, expression profile differences between PD and controls are much more modest and that genome-wide significant differences are restricted to the striatum and cerebral cortex. RNA (aRNA) was generated from 500ng of total RNA from the medulla (n=15 control brains, n=14 PD brains), striatum (n=15 control brains, n = 15 PD brains), frontal cortex (n=15 control brains, n = 11 PD brains) and cerebellum (n = 14 control brains, n=15 PD brains).
2011-07-21 | E-GEOD-28894 | biostudies-arrayexpress
Project description:In Parkinsonâ??s disease (PD), the progressive loss of substantia nigra dopamine cells has been associated with their vulnerability to oxidative stress, inflammation, and mitochondrial dysfunction. To identify multiple gene transcription alterations that may potentially underlie early stages of related degenerative processes in brain, we used the subcrhonic MPTP mouse model of PD and microarray analysis at 4 days post-MPTP when neurotoxic activity is maximal. Since PD results in gene changes throughout the brain, we assessed MPTP's effects in multiple regions: frontal cortex, striatum and midbrain. Experiment Overall Design: Mus musculus adults were randomly assigned to either MPTP or saline treatment groups. Brain regions of interest (frontal cortex, striatum and midbrain) were dissected from both groups for RNA extraction and hybridization on Affymetrix microarrays.
2008-10-26 | E-GEOD-7707 | biostudies-arrayexpress
Project description:Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum and cortex are functionally connected with increasing degrees of alpha-synuclein pathology in Parkinson's disease. Functional and causal pathway analysis of gene expression and proteomic alterations in these three regions revealed pathways that correlated with deposition of alpha-synuclein. Microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release and other changes were reflected across all brain regions. Importantly a subset of these changes were replicated in Parkinson's disease blood. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene gene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changes that accompany alpha-synculein pathology in Parkinson's disease, and may be instrumental in understanding and diagnosing Parkinson's disease progression. Substantia Nigra (3 normal, 3 PD), Striatum (6 normal, 6 PD), Cortex (5 normal, 5 PD), Cortex non-PD neurodegeneration (2 normal, 3 DLB). Note Sample X201264 was used both for Cortex normal and for Cortex nonPD normal
2014-09-01 | E-GEOD-54282 | biostudies-arrayexpress
Project description:The full complement of molecular pathways contributing to Parkinson’s disease (PD) pathogenesis remains unknown. Here, to address this issue, we began by using a high-resolution variant of functional magnetic resonance imaging (fMRI) to pinpoint brainstem regions differentially affected by, and resistant to, the disease. Then, relying on the imaging information as a guide, we profiled gene expression levels of postmortem brain samples and used a factorial statistical model to identify a disease related decrease in the expression of the polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a series of studies were performed to confirm the pathogenic relevance of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, while Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, we genotyped PD patients and controls and isolated a rare but novel variant in the SAT1 gene, although the functional significance of this genetic variant was not identified. Taken together, the results suggest that the polyamine pathway contributes to PD pathogenesis. Imaging-guided microarray In principle, gene expression profiling techniques like microarray are well suited to identify molecular pathways contributing to the pathogenesis of complex diseases. In practice, however, microarray applied to diseases of the brain present a number of analytic challenges. By identifying regions within the same brain structure that are differentially targeted by and resistant to a disease, imaging-guided microarray is an approach designed to address these limitations. Specifically, guided by the spatial information generated from high resolution functional imaging, a 2x2 factorial analysis-of-variance can be designed, including both within and between group factors, and this “double subtraction” model is effective in improving signal-to-noise in a microarray experiment. Relying on imaging findings, we harvested the DMNV from 6 postmortem brains with evidence of PD and from 5 control brains. The postmortem PD cases were evaluated for pathological changes (Lewy body-containing neurons and Lewy neurites evidenced with antibodies directed against α-synuclein aggregates) that matched the pattern proposed by Braak. We relied on the imaging results to identify a neighboring medullary region relatively unaffected by the disease to be used as a within-brain control. We decided on the inferior olivary nucleus (ION), because it is histologically identifiable, and harvested the ION from each of the 6 PD cases and 5 controls. Microarray techniques were used to generate gene expression profiles for each of the 22 tissue samples. A repeated-measures 2x2 factorial ANOVA model constructed for the imaging study was applied to the expression dataset, in which expression levels from two regions of the medulla (DMNV vs. ION) were included as the first within group factor, diagnosis (PD vs. controls) was the between group factor, and age and sex were included as covariates. Based on current literature, one of the top hits (SAT1) was investigated further to determine if it played a role in PD pathogenesis.
2010-08-19 | E-GEOD-19587 | biostudies-arrayexpress
Project description:Huntington’s disease (HD) involves marked early neurodegeneration in the striatum whereas the cerebellum is relatively spared despite the ubiquitous expression of full-length mutant huntingtin, implying that inherent tissue-specific differences determine susceptibility to the HD CAG mutation. To understand this tissue specificity, we compared early mutant huntingtin-induced gene expression changes in striatum to those in cerebellum in young Hdh CAG knock-in mice, prior to onset of evident pathological alterations. Endogenous levels of full-length mutant huntingtin caused qualitatively similar, but quantitatively different gene expression changes in the two brain regions. Importantly, the quantitatively different responses in striatum and cerebellum in mutant mice were well accounted for by the intrinsic molecular differences in gene expression between striatum and cerebellum in wild-type animals. Tissue-specific gene expression changes in response to the HD mutation, therefore, appear to reflect the different inherent capacities of these tissues to buffer qualitatively similar effects of mutant huntingtin. These findings highlight a role for intrinsic quantitative tissue differences in contributing to HD pathogenesis, and likely to other neurodegenerative disorders exhibiting tissue-specificity, thereby guiding the search for effective therapeutic interventions. Total RNA was isolated from striatum and cerebellum of Hdh CAG knock-in mice (HdhQ111/HdhQ111) and wild-type mice (Hdh+/Hdh+, 3~10 weeks) for gene expression profiling using Affymetrix MG430 2.0 arrays.
2011-08-22 | E-GEOD-9038 | biostudies-arrayexpress
Project description:We report single-nucleus transcriptomes from brain regions in 5 species: mice: Frontal Cortex, V1, Hippocampus, Striatum; common marmoset: 7 neocortical regions, Hippocampus, Striatum (Nucleus Accumbens, Caudate, Putamen); rhesus macaque: Prefrontal Cortex, V1; human: Prefrontal Cortex, V1, Striatum (Caudate); ferret: Prefrontal Cortex, V1, Striatum
2020-06-04 | GSE151761 | GEO
Project description:Huntington’s disease (HD) involves marked early neurodegeneration in the striatum whereas the cerebellum is relatively spared despite the ubiquitous expression of full-length mutant huntingtin, implying that inherent tissue-specific differences determine susceptibility to the HD CAG mutation. To understand this tissue specificity, we compared early mutant huntingtin-induced gene expression changes in striatum to those in cerebellum in young Hdh CAG knock-in mice, prior to onset of evident pathological alterations. Endogenous levels of full-length mutant huntingtin caused qualitatively similar, but quantitatively different gene expression changes in the two brain regions. Importantly, the quantitatively different responses in striatum and cerebellum in mutant mice were well accounted for by the intrinsic molecular differences in gene expression between striatum and cerebellum in wild-type animals. Tissue-specific gene expression changes in response to the HD mutation, therefore, appear to reflect the different inherent capacities of these tissues to buffer qualitatively similar effects of mutant huntingtin. These findings highlight a role for intrinsic quantitative tissue differences in contributing to HD pathogenesis, and likely to other neurodegenerative disorders exhibiting tissue-specificity, thereby guiding the search for effective therapeutic interventions.
2011-08-23 | GSE9038 | GEO
Project description:Despite being the second most common neurodegenerative disorder, little is known about Parkinson’s disease (PD) pathogenesis. A number of genetic factors predispose towards PD, among them mutations in GBA1, which encodes the lysosomal enzyme acid-β-glucosidase. We now perform non-targeted, mass spectrometry based quantitative proteomics on five brain regions from PD patients with a GBA1 mutation (PD-GBA) and compare to age- and sex-matched idiopathic PD patients and controls. Only two proteins were differentially-expressed in all five brain regions whereas significant differences were detected between the brain regions, with changes consistent with loss of dopaminergic neurons in the substantia nigra and activation of a number of pathways in the cingulate gyrus, including ceramide synthesis. Mitochondrial oxidative phosphorylation was inactivated to a larger extent in IPD samples compared to controls and to an even larger extent in PD-GBA. This is the first large-scale proteomics dataset generated for the study of PD-GBA.
2024-02-19 | PXD047134 | Pride
Project description:Patients with Alzheimer’s disease (AD) and Parkinson disease (PD) often have overlap in brain neuropathology and clinical presentation suggesting that these two diseases share common underlying mechanisms. Currently, the molecular events linking AD and PD are incompletely understood. Utilizing 10-plex Tandem Mass Tag (TMT) assays and MultiNotch MS3 mass spectrometry, we performed an unbiased quantitative proteomic analysis of post-mortem human brain tissues (n=80) from four different groups defined as healthy controls, AD, PD, and co-morbid AD/PD cases across two brain regions (frontal cortex and anterior cingulate gyrus). In total, we identified 11,840 protein groups representing 10,230 gene symbols, which map to ~65% of the protein coding genes in brain. The utility of including two reference standards in each TMT 10-plex assay to assess intra-batch and inter-batch variance is also described. Ultimately, this comprehensive human brain proteomic dataset serves as a valuable resource for various research endeavors including, but not limited to, the identification of protein signatures and neuro-centric signaling pathways that are common or distinct in AD and PD.
2018-02-07 | PXD007160 | Pride
Project description:In Parkinson’s disease (PD), the progressive loss of substantia nigra dopamine cells has been associated with their vulnerability to oxidative stress, inflammation, and mitochondrial dysfunction. To identify multiple gene transcription alterations that may potentially underlie early stages of related degenerative processes in brain, we used the subcrhonic MPTP mouse model of PD and microarray analysis at 4 days post-MPTP when neurotoxic activity is maximal. Since PD results in gene changes throughout the brain, we assessed MPTP's effects in multiple regions: frontal cortex, striatum and midbrain. Keywords: neurotoxic response
2008-10-21 | GSE7707 | GEO