Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single-cell profiling of limbic excitatory neurons reveals dysregulation of metabolic pathways in Parkinson’s disease

ABSTRACT: Parkinson’s disease (PD) is a common age-related neurodegenerative disorder that is pathologically characterized by the presence of Lewy bodies within neurons across several brain regions. Although the severe, selective degeneration of pigmented dopaminergic neurons in the midbrain results in a characteristic constellation of motor symptoms, how additional neuronal populations are affected in disease and contribute to neuropsychiatric symptoms remains unclear. The amygdala is one of the most frequent brain regions to harbor Lewy bodies in both PD and Alzheimer’s disease with co-existing alpha-synuclein pathology. To understand how neurons and glial cells are altered in this subcortical limbic area in PD, we performed single-nucleus RNA-sequencing (snRNA-seq) of patients and age-matched controls that yielded 168,270 transcriptomes following quality control measures. Through stringent differential gene expression analysis, we found transcriptional perturbations of genes linked to metabolic pathways in excitatory neurons, including upregulation of TFEB, but not inhibitory neurons or neural precursors. Additionally, we observed increased microglia with shifts towards activated states. Through bioinformatic integration of snRNA-seq with genetics studies, our findings suggest that PD risk factors act in cell-autonomous processes through both limbic excitatory neurons and midbrain dopaminergic neurons. Our findings define the selective vulnerability of excitatory neurons in the amygdala and may have implications for the understanding and treatment of non-movement symptoms in PD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295998 | GEO | 2026/04/29

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Spatial Multi-Omics Identifies Early Synaptic Pruning and Context-Specific Dopaminergic Vulnerability in Synucleinopathies

Project description:Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer’s disease (AD), and AD with Lewy body pathology (AD+LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD.

2026-06-09 | PXD062998 | Pride

RNA-seq of human midbrain organoid models of Parkinson's Disease

Project description:Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that is characterized by the selective loss of midbrain dopamine (DA)-producing neurons and the formation of α-synuclein (α-syn)-containing inclusions named Lewy bodies (LBs). Here, we report that the loss of glucocerebrosidase (GCase), coupled with α-syn overexpression, result in substantial accumulation of detergent-resistant α-syn aggregates and Lewy body-like inclusions (LBLIs) in human midbrain-like organoids (hMLOs). These LBLIs exhibit a highly similar structure to PD-associated LBs, by displaying a spherically symmetric morphology with an eosinophilic core, and containing α-syn and ubiquitin. Importantly, hMLOs generated from PD patient-derived inducible pluripotent stem cells (iPSCs) harboring SNCA triplication also exhibit subsequent degeneration of DA neurons and LBLI formation upon chronic GCase inhibitor treatment. Taken together, our hMLOs harbouring two major PD risk factors (GCase deficiency and overproduced α-syn) successfully recapitulate major pathophysiological signatures of the disease, and highlight the broad utility of brain organoid technology in modeling human neurodegenerative diseases.

2021-08-13 | E-MTAB-7302 | biostudies-arrayexpress

Caspase inhibition restores dopaminergic identity through the PKA–CREB–BDNF axis in Parkinson’s disease neurons

Project description:The progressive loss of dopaminergic identity in midbrain neurons is a hallmark of Parkinson’s disease (PD), contributing to synaptic dysfunction and neurodegeneration. However, the molecular mechanisms linking disease-specific stress to dopaminergic transcriptional failure remain poorly understood. Here, we used human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic neurons (mDAs) from sporadic PD patients to investigate early alterations in neuronal identity, plasticity, and survival. We found that PD-derived mDAs exhibit upregulation of phosphorylated α-synuclein, marked reductions in dopaminergic markers (TH, NURR1), deficient dopamine handling and impaired synaptogenesis. Transcriptomic and protein analyses revealed sustained activation of apoptotic caspases (caspase-3, -7) and downregulation of the PKA–CREB–BDNF signaling axis, which underpins dopaminergic differentiation and synaptic maturation. Pharmacological inhibition of caspases with Q-VD-OPh restored pCREB, BDNF, and downstream dopaminergic markers, leading to morphological recovery and functional synaptic rescue. Inhibition of PKA with H89 abrogated these effects, positioning the caspase–PKA–CREB cascade as a critical regulator of dopaminergic identity in PD neurons. These findings define a novel non-apoptotic role for caspases in disrupting the transcriptional program of mDAs and identify a druggable pathway capable of rescuing key aspects of dopaminergic function in a patient-derived cellular model. This work provides a mechanistic rationale for targeting caspase signaling in early-stage PD.

2026-06-08 | PXD066765 | Pride

Development of early-stage alpha-synucleinopathy is not governed by myelin status in mice of either sex

Project description:Lewy body disorders are characterized by alpha-synucleinopathic inclusions that tend to develop in neurons extending long, thin, and unmyelinated fibers. It is unknown if this selective vulnerability reflects poor myelination per se. We have observed that preformed fibrils (PFFs) of alpha-synuclein tend to induce pathology in gray matter, even when infused into regions penetrated by white matter bundles. In addition, we found that levels of insoluble, hyperphosphorylated alpha-synuclein correlate inversely with myelin markers in the postmortem amygdala of men—but not women—with Lewy body disease. Thus, we tested if myelin disruption with pharmacologic or genetic tools exacerbates alpha-synucleinopathic lesions in a model of early-stage, limbic Lewy body disease. In genetically outbred CD-1 mice infused with PFFs in the caudal olfactory bulb, the myelin-disruptor cuprizone caused subtle exacerbation of α-synucleinopathy, but without impacting PFF-induced neuron loss or behavior deficits. Furthermore, in C57BL/6J mice heterozygous for myelin basic protein (Mbp+/shi), PFF-induced increases in the insolubility and hyperphosphorylation of alpha-synuclein were not amplified and histological outcomes were not markedly exacerbated. Given our observations of inverse correlations between α-synucleinopathy and myelin markers in the human male amygdala, Lewy body disease may disrupt myelination, rather than poor myelination status regulating the emergence of limbic α-synucleinopathy. This new perspective is reinforced by suppressed expression of select oligodendrocytic markers in the amygdalae of men with Lewy body disease compared to women. Thus, resilient neurons may defy the initial development of Lewy-related pathologies due to properties unrelated to myelination per se.

2025-05-20 | GSE297212 | GEO

CHCHD2 Mutant Mice Link Mitochondrial Deficits to PD Pathophysiology

Project description:Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2, which causes late-onset symptoms indistinguishable from idiopathic PD. We observed pronounced mitochondrial disruption in substantia nigra (SN) dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift towards glycolysis, elevated mitochondrial ROS, and progressive accumulation of aggregated α-synuclein. In idiopathic PD, CHCHD2 gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.

2025-10-02 | GSE309202 | GEO

RNA-SEQ profiling of mouse whole midbrain and dopaminergic neurons from the mouse mid-brain

Project description:RNA-SEQ profiling of mouse whole midbrain and dopaminergic neurons from the mouse mid-brain Murine whole midbrain and murine midbrain dopaminergic neurons

2015-07-27 | E-GEOD-64526 | biostudies-arrayexpress

Transcriptomic analysis of early stage of alpha-synuclein accummulation in Parkinson's disease mouse model

Project description:The gene expression changes in dopaminergic neurons in PD mouse model has not been able to study due to lack of an approach in the collection of viable neurons from mouse brains. We utilized the established Ddc-hKO1 knock in mice and improved neural dissociation protocol accompanied with FACS to faciliate the collection of viable dopaminergic neurons. We performed intranigral injection with pre-formed alpha-synuclein fibril with G51D mutation on Snca to induce Lewy body-like structure accumulation. Dopaminergic neurons rom midbrain were collected at 7 weeks and 12 weeks post injection to reflect the early stage of PD progression. 2 brains were pooled as a single biological replicate. We performed gene ontology analysis using DAVID and GSEA analysis with pre-ranked in fold change. Both analysis shows that lipid metabolism associated gene sets were enriched in up-regulated genes in 7 weeks post-injection but remained unchange in expression in 12 weeks post-injection. Meanwhile, protein post-translational modifications related gene sets were enriched in up-regulated genes at 12 weeks post-injection but remained unchanged at 7 weeks post-injection. We showed that Fabp1 expression of was up-regulated in hKO1(+) cells and up-regulation of FABP1 in VTA & SNc region was confirmed by immunofluorescence staining.

2026-04-09 | GSE171580 | GEO

CYP46A1 promotes Parkinson’s disease

Project description:Parkinson’s disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of α-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of α-Syn via the XBP1‒LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD.

2025-01-23 | MTBLS11709 | MetaboLights

aCGH study of iPS cells from two normal subjects and two Parkinson's disease patients with parkin mutations

Project description:Parkinson's disease (PD) is defined by the degeneration of nigral dopaminergic (DA) neurons and can be caused by monogenic mutations of genes such as parkin. The lack of phenotype in parkin knockout mice suggests that human nigral DA neurons have unique vulnerabilities. Here we generate induced pluripotent stem cells from normal subjects and PD patients with parkin mutations. We demonstrate that loss of parkin in human midbrain DA neurons greatly increases the transcription of monoamine oxidases and oxidative stress, significantly reduces DA uptake and increases spontaneous DA release. Lentiviral expression of parkin, but not its PD-linked mutant, rescues these phenotypes. The results suggest that parkin controls dopamine utilization in human midbrain DA neurons by enhancing the precision of DA neurotransmission and suppressing dopamine oxidation. Thus, the study provides novel targets and a physiologically relevant screening platform for disease-modifying therapies of PD. Genomic DNA was isolated from each of the four lines of iPSCs and labeled with Cy5. Pooled sex mismatched normal human genomic DNA was labeled with Cy3. Both samples are hybridized together on RPCI 21K BAC aCGH array.

2012-01-21 | E-GEOD-35190 | biostudies-arrayexpress

RNA-Seq profiling of dopaminergic neurons from iPSCs of Parkinson's disease patients

Project description:The fact that Parkinsons disease (PD) can arise from numerous genetic mutations suggests a unifying molecular pathology underlying the various genetic backgrounds. In order to address this hypothesis, an integrated approach utilizing in vitro disease modeling and comprehensive transcriptome profiling was taken to advance our understanding of PD progression and the concordant downstream signaling pathways across divergent genetic predispositions. To model PD in vitro, neurons harboring disease-causing mutations were generated from patient-specific, induced pluripotent stem cells (iPSCs) and found to recapitulate several disease-related phenotypes. Signs of degeneration in PD midbrain dopaminergic (mDA) neurons were observed, reflecting the cardinal feature of PD. In addition, novel gene expression signatures were revealed for PD mDA neurons, providing molecular insights to disease phenotype observed in vitro, including oxidative stress vulnerability and altered neuronal activity. Notably, detailed transcriptome profiling of PD neurons showed that elevated RBFOX1, a gene previously linked to neurodevelopmental diseases, is responsible for a pattern of alternative RNA processing associated with PD-specific phenotypes in vitro.

2016-06-07 | E-MTAB-4586 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data