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A human single cell atlas of the substantia nigra reveals novel cell specific pathways associated with the genetic risk of Parkinson’s disease and neuropsychiatric disorders

ABSTRACT: A human single cell atlas of the substantia nigra reveals novel cell specific pathways associated with the genetic risk of Parkinson’s disease and neuropsychiatric disorders

PROVIDER: PRJNA589018 | ENA |

REPOSITORIES: ENA

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A human single cell atlas of the substantia nigra reveals novel cell specific pathways associated with the genetic risk of Parkinson’s disease and neuropsychiatric disorders

Project description:We describe the first human single-nuclei transcriptomic atlas for substantia nigra (SN), generated by sequencing ~ 17,000 nuclei from matched cortical and SN samples. We show that common genetic risk for Parkinson’s disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression including mitochondrial functioning, protein folding and ubiquitination pathways. We also identified a distinct cell-type association between PD risk and oligodendrocyte-specific expression implicating metabolic and gene expression regulation networks. Beyond PD, we find SN DaNs and GABAergic neurons to be associated with different neuropsychiatric disorders, particularly schizophrenia (SCZ) and bipolar disorder (BP). We identified distinct cortex/SN associations with SCZ genetic risk for both excitatory (synaptic functioning) and dopaminergic neurons (mitochondrial functioning and synaptic signalling). Conditional analyses shows that independent sets of loci associate distinct neuropsychiatric disorders with the same neuronal types. This atlas guides our aetiological understanding by associating SN cell-type expression profiles with specific disease risk.

2020-01-07 | GSE140231 | GEO

Transcriptional and interactome network analyses of Substantia Nigra in progressive stages of Parkinson’s disease

Project description:We analyzed the transcriptomic profile of post-mortem substantia nigra explants from controls, intermediate - Braak 3 (BK3) and 4 (BK4) - stages of Parkinson’s disease in order to investigate how gene-gene interaction patterns vary along disease development. The comparative transcriptional networks analyses indicate that the main hubs in CT network showed less gene-gene connections in BK3 and BK4 networks, probably reflecting changes in SN cell metabolism, population and density along PD stages.

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Transcriptomic profiling of substantia nigra and putamen in Parkinson’s disease

Project description:We report RNA sequencing results of human substantia nigra and putamen samples from Parkinson's disease patients and controls. Each substantia nigra sample is the result of pooling brain tissue from two individuals with the same , while each putamen sample is the result of pooling brain tissue from three individuals. We found 354 differentially expressed genes (DEGs) in the SN of PD patients compared to age-matched controls, while we observed 261 DEGs in the putamen samples. The top-enriched pathways from the SN were associated with “protein folding” and “neurotransmitter transport”, and the putamen DEGs with “synapse organization”. In summary, our data confirms the key role of protein folding and neuronal degeneration in the pathology of PD, and highlights new genes and pathways that have not yet been explored in the context of PD.

2020-09-02 | GSE136666 | GEO

Transcriptomic profiling of substantia nigra and putamen in Parkinson’s disease

Project description:Transcriptomic profiling of substantia nigra and putamen in Parkinson’s disease

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Polyomic analyses of dopaminergic neurons isolated from human substantia nigra in Parkinson’s disease: An exploratory study.

Project description:Dopaminergic neurons of the substantia nigra pars compacta selectively and progressively degenerate in Parkinson’s disease. Until now, molecular analyses of dopaminergic neurons in PD have been limited to genomic and transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined polyomic study examining the protein profile of these neurons, is currently available. In this exploratory study, we used laser microdissection to extract dopaminergic neurons from 10 human SNpc samples obtained at autopsy in Parkinson’s disease patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nano-LC-MS/MS, respectively, and the differential expression between Parkinson’s disease and control group was assessed. Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This polyomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in Parkinson’s disease, such as LRP2, PNMT, CXCR4, MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. This is the first exploratory study analyzing both gene and protein expression of LMD-dissected neurons from substantia nigra pars compacta in Parkinson’s disease.

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Transcriptomic profiling of mouse substantia nigra tissue by RNA-seq

Project description:Transcriptomic profiling of substantia nigra of wild type (WT) and Tpbg knockout (KO) mice (RNA-seq)

2021-12-01 | GSE178400 | GEO

Systematic meta-analysis and replication of genome-wide expression studies of Parkinson’s disease: 4

Project description:Analysis of substantia nigra from postmortem brains of 4 patients with Parkinson’s disease (PD). Results provide insight into the molecular processes perturbed in the PD substantia nigra.

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Time Course of Gene Expression in the Substantia Nigra in Response to Intrastriatal 6-hydroxydopamine in the rat.

Project description:The 6-hydroxydopamine (6OHDA) rat model of parkinsonism is among the first, and most commonly used, animal models of Parkinson’s disease. It provides insight into the compensatory changes that occur in the brain after dopamine (DA) neuron degeneration. In order to better define the consequences of substantia nigra DA neuron loss on the neural and glial populations during and following nigrostriatal degeneration, tissue was collected and evaluated from the substantia nigra of 6OHDA or vehicle treated, or naïve rats at 1, 2, 4, 6 & 16 weeks. Comprehensive gene expression analysis was conducted to detect significant differences in gene expression. Comparisons were conducted within the same treatment groups over time as well as across treatments within the same post-treatment interval. Longitudinal expression patterns were parsed using a k-means clustering algorithm as a method for finding patterns indicative of neuronal loss, upregulation in response to lesion or surgical damage exclusive of lesion. Tissue was collected from the substantia nigra of 6OHDA treated, sham and naïve rats at 1, 2, 4, 6 & 16 weeks post-treatment. A unilateral striatal lesion was employed that results in a 99% striatal DA reduction and an 80% loss of DA neurons in the substantia nigra. 6OHDA lesions were confirmed via catecholamine quantitation by HPLC. RNA integrity was assessed with an Agilent 2100 Bioanalyzer with minimum RIN acceptance criteria of 8.0. Multidimensional plots and Pearson Correlations were used to establish group/treatment homogeneity. Tissue was subjected to comprehensive gene expression analysis using the Affymetrix Rat Gene 1.0ST array.

2014-06-21 | E-GEOD-58710 | biostudies-arrayexpress

Control human putamen and Substantia Nigra

Project description:The study is affiliated to the UKBEC sample of healthy human putamen and substantia nigra phenotype. The gender is from both male and female samples of the the phenotype.

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Proteomic analysis of substantia nigra

Project description:Proteomic analysis of human substantia nigra using protein and peptide fractionations strategies coupled to nanoLC-MS/MS

2015-08-17 | PXD001496 | Pride