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Unravelling cell type-specific responses to Parkinson’s Disease at single cell resolution

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Martirosyan, Araks 
Ansari, Rizwan 
Pestana, Francisco 
Hebestreit, Katja 
Gasparyan, Hayk 


Parkinson’s Disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is loss of dopaminergic neurons and the presence of aggregated α-synuclein, primarily in the substantia nigra pars compacta (SNpc) of the midbrain. However, the molecular mechanisms that underlie the pathology in different cell types is not currently understood. Here, we present a single nucleus transcriptome analysis of human post-mortem SNpc obtained from 15 sporadic Parkinson’s Disease (PD) cases and 14 Controls. Our dataset comprises ∼84K nuclei, representing all major cell types of the brain, allowing us to obtain a transcriptome-level characterization of these cell types. Importantly, we identify multiple subpopulations for each cell type and describe specific gene sets that provide insights into the differing roles of these subpopulations. Our findings reveal a significant decrease in neuronal cells in PD samples, accompanied by an increase in glial cells and T cells. Subpopulation analyses demonstrate a significant depletion of tyrosine hydroxylase (TH) enriched astrocyte, microglia and oligodendrocyte populations in PD samples, as well as TH enriched neurons, which are also depleted. Moreover, marker gene analysis of the depleted subpopulations identified 28 overlapping genes, including those associated with dopamine metabolism (e.g., ALDH1A1, SLC6A3 & SLC18A2). Overall, our study provides a valuable resource for understanding the molecular mechanisms involved in dopaminergic neuron degeneration and glial responses in PD, highlighting the existence of novel subpopulations and cell type-specific gene sets.


Acknowledgements: The authors thank the tissue donors and their families, Oregon Brain Bank and the funders that made this research possible. We would like to thank Sarah Field for proof-reading and assessing the structure of the manuscript draft. Figure 1A was created using BioRender.

Funder: VIB Tech Watch


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Molecular Neurodegeneration

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BioMed Central
Stichting Alzheimer Onderzoek (20200034, 2020/017)
Fundação para a Ciência e a Tecnologia (2020.08750BD)
Fonds Wetenschappelijk Onderzoek (G0F8516N, G065721N)
KU-Leuven Internal Funding (C14/17/107, C14/22/132, C3/20/057)
Bit Bio Ltd (RRAG/257)
Welcome Trust (RG86251)
Open Targets (OTAR2052)
European Commission (H2020 WIDESPREAD-2018-2020-6, NCBio, 951923)
UK Dementia Research Institute (RRZA/175)