Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease
Several studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, studies using singlecell profiling techniques have begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work h...
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eLife Sciences Publications Ltd
2025-05-01
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| author | Zachary Gaertner Cameron Oram Amanda Schneeweis Elan Schonfeld Cyril Bolduc Chuyu Chen Daniel Dombeck Loukia Parisiadou Jean-Francois Poulin Rajeshwar Awatramani |
| author_facet | Zachary Gaertner Cameron Oram Amanda Schneeweis Elan Schonfeld Cyril Bolduc Chuyu Chen Daniel Dombeck Loukia Parisiadou Jean-Francois Poulin Rajeshwar Awatramani |
| author_sort | Zachary Gaertner |
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| description | Several studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, studies using singlecell profiling techniques have begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work has shown that molecularly defined DA subtypes within the substantia nigra (SNc) display distinctive anatomic and functional properties, and differential vulnerability in Parkinson’s disease (PD). Based on these provocative results, a granular understanding of these putative subtypes and their alterations in PD models, is imperative. We developed an optimized pipeline for single-nuclear RNA sequencing (snRNA-seq) and generated a high-resolution hierarchically organized map revealing 20 molecularly distinct DA neuron subtypes belonging to three main families. We integrated this data with spatial MERFISH technology to map, with high definition, the location of these subtypes in the mouse midbrain, revealing heterogeneity even within neuroanatomical sub-structures. Finally, we demonstrate that in the preclinical LRRK2G2019S knock-in mouse model of PD, subtype organization and proportions are preserved. Transcriptional alterations occur in many subtypes including those localized to the ventral tier SNc, where differential expression is observed in synaptic pathways, which might account for previously described DA release deficits in this model. Our work provides an advancement of current taxonomic schemes of the mouse midbrain DA neuron subtypes, a high-resolution view of their spatial locations, and their alterations in a prodromal mouse model of PD. |
| format | Article |
| id | doaj-art-174d63355deb42afa8a7afd93b7ba05a |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-174d63355deb42afa8a7afd93b7ba05a2025-08-20T03:52:48ZengeLife Sciences Publications LtdeLife2050-084X2025-05-011310.7554/eLife.101035Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s diseaseZachary Gaertner0https://orcid.org/0000-0002-1760-6549Cameron Oram1Amanda Schneeweis2https://orcid.org/0000-0003-4141-6064Elan Schonfeld3https://orcid.org/0000-0001-7368-1562Cyril Bolduc4Chuyu Chen5https://orcid.org/0000-0001-5666-5173Daniel Dombeck6https://orcid.org/0000-0003-2576-5918Loukia Parisiadou7https://orcid.org/0000-0002-2569-4200Jean-Francois Poulin8https://orcid.org/0000-0002-1039-4985Rajeshwar Awatramani9https://orcid.org/0000-0002-0713-2140Northwestern University Feinberg School of Medicine, Dept of Neurology, Chicago, United States; Northwestern University, Dept of Neurobiology, Evanston, United States; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United StatesMcGill University (Montreal Neurological Institute), Faculty of Medicine and Health Sciences, Dept of Neurology and Neurosurgery, Montreal, CanadaNorthwestern University Feinberg School of Medicine, Dept of Neurology, Chicago, United States; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United StatesNorthwestern University Feinberg School of Medicine, Dept of Neurology, Chicago, United StatesMcGill University (Montreal Neurological Institute), Faculty of Medicine and Health Sciences, Dept of Neurology and Neurosurgery, Montreal, CanadaAligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United States; Northwestern University Feinberg School of Medicine, Dept of Pharmacology, Chicago, United StatesNorthwestern University, Dept of Neurobiology, Evanston, United States; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United StatesAligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United StatesMcGill University (Montreal Neurological Institute), Faculty of Medicine and Health Sciences, Dept of Neurology and Neurosurgery, Montreal, CanadaNorthwestern University Feinberg School of Medicine, Dept of Neurology, Chicago, United States; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United StatesSeveral studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, studies using singlecell profiling techniques have begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work has shown that molecularly defined DA subtypes within the substantia nigra (SNc) display distinctive anatomic and functional properties, and differential vulnerability in Parkinson’s disease (PD). Based on these provocative results, a granular understanding of these putative subtypes and their alterations in PD models, is imperative. We developed an optimized pipeline for single-nuclear RNA sequencing (snRNA-seq) and generated a high-resolution hierarchically organized map revealing 20 molecularly distinct DA neuron subtypes belonging to three main families. We integrated this data with spatial MERFISH technology to map, with high definition, the location of these subtypes in the mouse midbrain, revealing heterogeneity even within neuroanatomical sub-structures. Finally, we demonstrate that in the preclinical LRRK2G2019S knock-in mouse model of PD, subtype organization and proportions are preserved. Transcriptional alterations occur in many subtypes including those localized to the ventral tier SNc, where differential expression is observed in synaptic pathways, which might account for previously described DA release deficits in this model. Our work provides an advancement of current taxonomic schemes of the mouse midbrain DA neuron subtypes, a high-resolution view of their spatial locations, and their alterations in a prodromal mouse model of PD.https://elifesciences.org/articles/101035Lrrk2dopaminetranscriptomicssubtypesspatialParkinson's disease |
| spellingShingle | Zachary Gaertner Cameron Oram Amanda Schneeweis Elan Schonfeld Cyril Bolduc Chuyu Chen Daniel Dombeck Loukia Parisiadou Jean-Francois Poulin Rajeshwar Awatramani Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease eLife Lrrk2 dopamine transcriptomics subtypes spatial Parkinson's disease |
| title | Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease |
| title_full | Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease |
| title_fullStr | Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease |
| title_full_unstemmed | Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease |
| title_short | Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease |
| title_sort | molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a lrrk2g2019s model of parkinson s disease |
| topic | Lrrk2 dopamine transcriptomics subtypes spatial Parkinson's disease |
| url | https://elifesciences.org/articles/101035 |
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