Single-Cell Transcriptomics and In Situ Morphological Analyses Reveal Microglia Heterogeneity Across the Nigrostriatal Pathway
Open accessAbstract
Microglia are the resident immune effector cells of the central nervous system (CNS) rapidly reacting to various pathological stimuli to maintain CNS homeostasis. However, microglial reactions in the CNS may also worsen neurological disorders. Hence, the phenotypic analysis of microglia in healthy tissue may identify specific poised subsets ultimately supporting or harming the neuronal network. This is all the more important for the understanding of CNS disorders exhibiting regional-specific and cellular pathological hallmarks, such as many neurodegenerative disorders, including Parkinson’s disease (PD). In this context, we aimed to address the heterogeneity of microglial cells in susceptible brain regions for PD, such as the nigrostriatal pathway. Here, we combined single-cell RNA-sequencing with immunofluorescence analyses of the murine nigrostriatal pathway, the most affected brain region in PD. We uncovered a microglia subset, mainly present in the midbrain, displaying an intrinsic transcriptional immune alerted signature sharing features of inflammation-induced microglia. Further, an in situ morphological screening of inferred cellular diversity showed a decreased microglia complexity in the midbrain when compared to striatum. Our study provides a resource for the identification of specific microglia phenotypes within the nigrostriatal pathway, which may be relevant in PD.
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A common genetic cause of PD are mutations of the LRRK2 gene, which is predominantly expressed in the CNS by MF.
“Specifically, a common genetic cause of PD are mutations of the leucine rich repeat kinase 2 (LRRK2) gene 73 which is predominantly expressed in the CNS by M F .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [73]
The Introduction and Discussion discuss Parkinson’s disease and microglia, but do not address LRRK2 mutations or which CNS cells predominantly express LRRK2. Searches of our full-text copy for “LRRK2” and its expanded name found no relevant passage; the copy therefore cannot verify the attributed claim. (LLM, conf=0.75)
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Self-citation
- Authors
- Uriarte Huarte, O., Kyriakis, D., Heurtaux, T., Pires-Afonso, Y., Grzyb, K., Halder, R., Buttini, M., Skupin, A., Mittelbronn, M., & Michelucci, A.
- Affiliations
- University of Luxembourg (LU)
- Corresponding author
- Michelucci, Alessandro
- ORCID
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2021-03-29
- Volume
- 12
- Pages
- 639613-639613
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC8039119
- OpenAlex
- W3142593804
- Cited by
- 52
- References
- 79
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 11 · 2023: 9 · 2022: 14 · 2021: 2 · 2012: 1
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fonds National de la Recherche Luxembourg (PRIDE15/10675146/CANBIO, C14/BM/7975668/CaSCAD , INTER/DFG/17/11583046)
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- nigrostriatal pathway, Parkinson's disease, microglial phenotype, midbrain, striatum, microglial morphology, neurodegeneration, single-cell transcriptomics
- MeSH terms
- Animals, Corpus Striatum, Female, Inflammation, Mesencephalon, Neurons, Parkinson Disease, Phenotype, Transcription, Genetic, Sequence Analysis, RNA, Microglia, Mice, Single-Cell Analysis, Transcriptome
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