Transcriptomic atlas of midbrain dopamine neurons uncovers differential vulnerability in a Parkinsonism lesion model
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ABSTRACT:
PROVIDER: PRJNA978334 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24787006_1.fastq.gz | Fastqsanger.gz | |||
| SRR24787006_2.fastq.gz | Fastqsanger.gz | |||
| SRR24787007_1.fastq.gz | Fastqsanger.gz | |||
| SRR24787007_2.fastq.gz | Fastqsanger.gz | |||
| SRR24787008_1.fastq.gz | Fastqsanger.gz |
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Project description:Midbrain dopamine (mDA) neurons comprise a diverse group of cells with unique innervation targets and functions. This is illustrated by the selective sensitivity of mDA neurons of the substantia nigra compacta (SNc) in patients with Parkinson’s disease, while those in the ventral tegmental area (VTA) are relatively spared. Here we used single nuclei RNA sequencing (snRNA-seq) of approximately 70,000 mouse midbrain cells to build a high-resolution atlas of mouse mDA neuron diversity at the molecular level. The results showed that differences between mDA neuron groups could best be understood as a continuum without sharp differences between subtypes. Thus, we assigned mDA neurons to several “territories” and “neighborhoods” within a shifting gene expression landscape where boundaries are gradual rather than discrete. Based on the enriched gene expression patterns of these territories and neighborhoods, we were able to localize them in the adult mouse midbrain. Moreover, because the underlying mechanisms for the variable sensitivities of diverse mDA neurons to pathological insults are not well understood, we analyzed surviving neurons after partial 6-hydroxydopamine (6-OHDA) lesions to unravel gene expression patterns that correlate with mDA neuron vulnerability and resilience. Together, this atlas provides a basis for further studies on the neurophysiological role of mDA neurons in health and disease.
2023-10-26 | GSE233866 | GEO
Project description:Midbrain dopamine (mDA) neurons comprise diverse cells with unique innervation targets and functions. This is illustrated by the selective sensitivity of mDA neurons of the substantia nigra compacta (SNc) in patients with Parkinson's disease, while those in the ventral tegmental area (VTA) are relatively spared. Here, we used single nuclei RNA sequencing (snRNA-seq) of approximately 70,000 mouse midbrain cells to build a high-resolution atlas of mouse mDA neuron diversity at the molecular level. The results showed that differences between mDA neuron groups could best be understood as a continuum without sharp differences between subtypes. Thus, we assigned mDA neurons to several 'territories' and 'neighborhoods' within a shifting gene expression landscape where boundaries are gradual rather than discrete. Based on the enriched gene expression patterns of these territories and neighborhoods, we were able to localize them in the adult mouse midbrain. Moreover, because the underlying mechanisms for the variable sensitivities of diverse mDA neurons to pathological insults are not well understood, we analyzed surviving neurons after partial 6-hydroxydopamine (6-OHDA) lesions to unravel gene expression patterns that correlate with mDA neuron vulnerability and resilience. Together, this atlas provides a basis for further studies on the neurophysiological role of mDA neurons in health and disease.
| S-EPMC11001297 | biostudies-literature
Project description:Parkinson’s disease (PD) is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but the pathophysiological mechanisms that precede and drive their death remain unknown. The activity of DA neurons is likely altered in PD, but we understand little about if or how chronic changes in activity may contribute to degeneration. To address this question, we developed a chemogenetic (DREADD) mouse model to chronically increase DA neuron activity, and confirmed this increase using ex vivo electrophysiology. Chronic hyperactivation of DA neurons resulted in prolonged increases in locomotor activity during the light cycle and decreases during the dark cycle, consistent with chronic changes in DA release and circadian disturbances. We also observed early, preferential degeneration of SNc projections, recapitulating the PD hallmarks of selective vulnerability of SNc axons and the comparative resilience of ventral tegmental area axons. This was followed by eventual loss of midbrain DA neurons. Continuous DREADD activation resulted in a sustained increase in baseline calcium levels, supporting a role for increased calcium in the neurodegeneration process. Finally, spatial transcriptomics from DREADD mice examining midbrain DA neurons and striatal targets, and cross-validation with human patient samples, provided insights into potential mechanisms of hyperactivity-induced toxicity and PD. Our results thus reveal the preferential vulnerability of SNc DA neurons to increased neural activity, and support a potential role for increased neural activity in driving degeneration in PD.
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Project description:The human midbrain-like organoid (hMLO) is a key model system for investigating pathological features of Parkinson’s disease (PD), yet how its molecular landscape relates to cellular vulnerability in PD remains unclear. We performed an in-depth single-cell characterization of our previously established hMLO model up to 150 days in vitro. Our hMLOs exhibited various physiological cell types and broad topographical patterning that resemble that of human fetal midbrain. We further identified four distinct dopamine-producing neuron (DaN) subtypes whose molecular profiles span a key transcriptomic axis in the selective vulnerability of DaNs in PD. Deletion of PARK7, a highly penetrant PD-causing gene, from hMLOs induced cell type-dependent molecular perturbations in mitochondrial activity and synapse biology, and recapitulated PD pathophysiology including α-synuclein aggregation, Lewy Body-like inclusions and DaN degeneration with extended culture. This study highlights the utility of our hMLO model in manifesting pathological features and cell type-specific vulnerability, enabling mechanistic studies into PD pathophysiology.
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Project description:The human midbrain-like organoid (hMLO) is a key model system for investigating pathological features of Parkinson’s disease (PD), yet how its molecular landscape relates to cellular vulnerability in PD remains unclear. We performed an in-depth single-cell characterization of our previously established hMLO model up to 150 days in vitro. Our hMLOs exhibited various physiological cell types and broad topographical patterning that resemble that of human fetal midbrain. We further identified four distinct dopamine-producing neuron (DaN) subtypes whose molecular profiles span a key transcriptomic axis in the selective vulnerability of DaNs in PD. Deletion of PARK7, a highly penetrant PD-causing gene, from hMLOs induced cell type-dependent molecular perturbations in mitochondrial activity and synapse biology, and recapitulated PD pathophysiology including α-synuclein aggregation, Lewy Body-like inclusions and DaN degeneration with extended culture. This study highlights the utility of our hMLO model in manifesting pathological features and cell type-specific vulnerability, enabling mechanistic studies into PD pathophysiology.
2025-12-04 | GSE271116 | GEO
Project description:The human midbrain-like organoid (hMLO) is a key model system for investigating pathological features of Parkinson’s disease (PD), yet how its molecular landscape relates to cellular vulnerability in PD remains unclear. We performed an in-depth single-cell characterization of our previously established hMLO model up to 150 days in vitro. Our hMLOs exhibited various physiological cell types and broad topographical patterning that resemble that of human fetal midbrain. We further identified four distinct dopamine-producing neuron (DaN) subtypes whose molecular profiles span a key transcriptomic axis in the selective vulnerability of DaNs in PD. Deletion of PARK7, a highly penetrant PD-causing gene, from hMLOs induced cell type-dependent molecular perturbations in mitochondrial activity and synapse biology, and recapitulated PD pathophysiology including α-synuclein aggregation, Lewy Body-like inclusions and DaN degeneration with extended culture. This study highlights the utility of our hMLO model in manifesting pathological features and cell type-specific vulnerability, enabling mechanistic studies into PD pathophysiology.
2025-12-04 | GSE271115 | GEO
Project description:Human pluripotent stem cells (hPSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of hPSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However the effective use of hPSCs for cell therapy has lagged far behind. While mouse PSC-derived DA neurons have shown efficacy in models of Parkinson’s disease, DA neurons derived from human PSCs generally display poor in vivo performance. There are also considerable safety concerns for hPSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor plate-based strategy for the derivation of human DA neurons that efficiently engraft, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor plate precursors are derived from hPSCs in days following exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signaling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive in vitro molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of hPSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in PD animal models in three host species. Long-term engraftment in 6-OHDA-lesioned mouse and rats demonstrates robust survival of midbrain DA neurons, complete restoration of amphetamine-induced rotation behavior and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into Parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models tested indicate considerable promise for the development of cell based therapies in PD. Differentiated hESC with three conditions (LSB, LSB/S/F8, LSB/S/F8/CHIR) were subjected to RNA extraction in specific timepoint (day 0, 1, 3, 5, 7, 11, 13, 25) and hybridization on Illumina microarrays. Each sample has 3 or 4 biological repeats. Based on previous study* of dual SMAD inhibition neural induction, we developed new midbrain dopamine neuron protocol. It depends on time specific treatment of below factors (LSB/S/F8/CHIR): L (LDN193189 (BMP inhibitor) , day 0-11), SB (SB431542 (TGF-b signal inhibitor), day 0-5), S (SHH + Purmorphamine (Smo agonist), day 1-7), F8 (FGF8, day 1-7) and CHIR (CHIR99021 (GSK3b inhibitor), day 3-13) LSB and LSB/S/F8 are limited control conditions of dual SMAD only (LSB) or traditional patterning with Sonic and FGF (LSB/S/F8) *Chambers,S.M. et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27, 275-280 (2009).
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Project description:We report a novel midbrain dopamine neuron derivation protocol from human pluripotent stem cells (hPSC)s based on a two-step WNT signaling activation strategy. By comparing next-generation sequencing (NGS) derived transcriptome profiling (RNA-seq) of dopamine neuron differentiated cells derived from hPSC with different concentration of Chir-boosting (day4 – day9) measured at day 11 including hPSC, we find that CHIR-boosting improves expression of midbrain markers such as EN1 while minimizing expression of contaminating posterior (hindbrain) and anterior (diencephalic) lineage markers. Furthermore, gene expression analysis from RNA-seq study confirmed the progressive differentiation and maturation of Boost CHIR treated precursors into mDA neurons by day 30 of differentiation. The protocol presented here is the basis for clinical grade dopamine neuron production and preclinical safety and efficacy studies.
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