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The spatial landscape of glial pathology and T-cell response in Parkinson’s disease substantia nigra [snRNAseq]

ABSTRACT: Recent evidence, including identification of specific peripheral T-cell receptor sequences, indicates the adaptive immune response is associated with disease pathogenesis. However, the properties of T-cells in the brain regions where neurons degenerate are uncharacterized. We have analyzed the identities and interactions of T-cells in PD in post-mortem brain tissue using single nucleus RNA sequencing, spatial transcriptomics and T-cell receptor sequencing. We found that T-cells in the substantia nigra of PD brain donors exhibit a CD8+ resident memory phenotype, increased clonal expansion, and altered spatial relationships with astrocytes, myeloid cells, and endothelial cells. We also describe regional differences in astrocytic responses to neurodegeneration. Our findings nominate potential molecular and cellular candidates that allow a deeper understanding of the pathophysiology of neurodegeneration in PD. Together, our work represents a major single nucleus and spatial transcriptional resource for the fields of neurodegeneration and PD

ORGANISM(S): Homo sapiens

PROVIDER: GSE253462 | GEO | 2025/07/09

REPOSITORIES: GEO

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The spatial landscape of glial pathology and T-cell response in Parkinson’s disease substantia nigra [pdtcrseq]

Project description:Recent evidence, including identification of specific peripheral T-cell receptor sequences, indicates the adaptive immune response is associated with disease pathogenesis. However, the properties of T-cells in the brain regions where neurons degenerate are uncharacterized. We have analyzed the identities and interactions of T-cells in PD in post-mortem brain tissue using single nucleus RNA sequencing, spatial transcriptomics and T-cell receptor sequencing. We found that T-cells in the substantia nigra of PD brain donors exhibit a CD8+ resident memory phenotype, increased clonal expansion, and altered spatial relationships with astrocytes, myeloid cells, and endothelial cells. We also describe regional differences in astrocytic responses to neurodegeneration. Our findings nominate potential molecular and cellular candidates that allow a deeper understanding of the pathophysiology of neurodegeneration in PD. Together, our work represents a major single nucleus and spatial transcriptional resource for the fields of neurodegeneration and PD

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The spatial landscape of glial pathology and T-cell response in Parkinson’s disease substantia nigra [ST]

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Single-Cell Transcriptomics of Human Substantia Nigra in Parkinson's Disease

Project description:Parkinson’s disease (PD) is the most common neurodegenerative movement disorder with unknown etiology. Loss of neuromelanin-containing dopaminergic (DA) neurons in the substanstia nigra (SN) is the hallmark of PD neuropathology. Here we performed single-nucleus RNA sequencing (snRNA-seq) of nuclei from the postmortem SN of control and idiopathic PD patients across various disease stages. The resulting transcriptomic atlas revealed a landscape of cellular alterations associated with disease progression in PD.

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

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Transcriptome-wide changes in the Substantia Nigra following Deep Brain Stimulation in the Subthalamic Nuecleus of a PD rat model.

Project description:In this study we identify the gene espression changes that occur in the substantia nigra in a Parkinson's Disease (PD) rat model with and without deep brain stimulation (DBS). A rat model of PD was created as previously described by stereotacticaly injecting an AAV-expressing the human A53T_mutated form of a-Synuclein into the Substantia Nigra of adult rats, while control rats were injected with empty vector (EV). These mice exhibit neurodegeneration in the Substantia Nigra and Parkinson-like behaviour phenotypes. Sixteen weeks after the injection, RNA was isolated from the Substantia Nigra and Striatum. Single-end 75nt high throughput sequencing were performed on libraries prepared from the RNA. We identified over 200 genes that were differentially expressed between control and Parkinson's ratswith a log2 fold-change > |0.6|. These genes were enriched for terms related to immune activation. The genes associated with these GO terms tended to be up-regulated in the Parkinson's rats suggesting that brain-localized immune cells are more activated in Parkinson's disease. Interestingly in the rats treated with DBS, these immune-related genes were comparable to control animals.

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Transcriptional interaction network analyses in dorsal nucleus of vagus nerve, locus coeruleus and substantia nigra in Parkinson's disease

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Transcriptional interaction network analyses in dorsal nucleus of vagus nerve, locus coeruleus and substantia nigra in Parkinson's disease

2015-01-11 | GSE43490 | GEO

Transcriptomics analysis of post-mortem substantia nigra samples from Parkinson’s disease patients and controls.

Project description:Purpose: Parkinson’s disease (PD) is one of the most common neurological movement disorders. In the incidence and the clinical features of PD, significant gender differences have been observed. While males have a higher disease prevalence and are more frequently affected by muscle rigidity, females present more often with disabling tremors. The molecular mechanisms behind these disease-associated gender differences are still largely unknown, and a detailed understanding of the factors involved may open new avenues for pharmacological disease modification. Methods: To address this gap, we have conducted a meta-analysis of disease-associated molecular gender differences in brain transcriptomics data from PD case/control studies. We studied gender-dependent expression changes in individual genes and using systems level pathway and network analyses to identify coordinated gender-related molecular alterations. In each analysis, both gender-specific changes (significant alteration in only one gender) and gender-dimorphic changes (changes in both genders, but with opposite direction) were identified. Results: These analyses revealed significant disease-associated sex differences in immune response processes and mitochondrial pathways, and highlight regulatory factors, such as the transcription factor NR4A2, whose activity changes can explain ensuing alterations propagated through gene regulatory cascades. Overall, significant gender disparities were observed in PD-associated transcriptomic changes, resulting in coordinated modulations of molecular processes. Among the regulatory factors involved, NR4A2 has previously been reported to harbor rare mutations in familial PD and its pharmacological activation conferred neuroprotective effects in toxin-induced models of Parkinsonism. NR4A2 may therefore be of interest as a candidate target for further preclinical studies on addressing gender-related pathological features of PD.

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Next generation sequencing reveals upregulation of the lncRNA LINC-PINT in the substantia nigra of human Parkinson's disease patients compared to control donors

Project description:Parkinson's disease (PD) is the second most common neurodegenerative disease, involving the selecive death of dopaminergic neurons in the substantia nigra pars compacta brain region. Here, we performed next generation sequencing on RNA extracted from human substantia nigra tissue. The samples, acquired from the Netherland's Brain Bank, were taken post-mortem from PD and non-PD control donors. Analysis of the data revealed an upregulation of lncRNA LINC-PINT in PD substantia nigra. LINC-PINT interracts with the Polycomb Repressive Complex 2 (PRC2), inhibiting the tracription of multiple targets. Correspondingly, analysis of the data revealed that targets of PRC2 displayed larger disease-associated differences as compared to other genes, as well as enrichment for downregulation, suggesting that the differential expression of LINC-PINT in PD effects LINC-PINT/PRC2 interaction as well.

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