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Defining specific cell states of MPTP-induced Parkinson's disease by single-nucleus RNA sequencing

ABSTRACT: Parkinson’s disease (PD), a neurodegenerative disease with the impairment of movement execution that is related to age, genetic and environmental factors. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine (MPTP) is a neurotoxin widely used to induce PD models, but the effect of MPTP on cell-gene of PD has not been fully elucidated. By single-nucleus RNA sequencing, we uncovered the PD-specific cells and revealed remarkable changes in their cellular states, including astrocytosis, endothelial cells absence, as well as a cluster of PD-exclusive medium spiny neuron cells. Furthermore, trajectory analysis of astrocyte and endothelial cells populations predicted candidate target gene sets that might be associated with PD. Notably, the detailed regulatory roles of astrocyte-specific transcription factors Dbx2 and Sox13 in PD were first revealed in our work. Finally, we characterized the cell-cell communications of PD-specific cells and found that the overall communication strength was enhanced in PD compared with matched control, especially the signaling pathways of NRXN and NEGR. Our work provides comprehensive overview on the changes of cellular states of the MPTP-induced mouse brain.

ORGANISM(S): Mus musculus

PROVIDER: GSE205367 | GEO | 2022/08/10

REPOSITORIES: GEO

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Project description:Implications for neuroprotection in Parkinson's disease Parkinson’s disease and its characteristic symptoms are thought to arise from the progressive degeneration of specific midbrain dopamine (DA) neurons. In humans, DA neurons of the substantia nigra (SN) and their projections to the striatum show selective vulnerability, while neighboring DA neurons of the ventral tegmental area (VTA) are relatively spared from degeneration. This pattern of cell loss is mimicked in humans, primates, and certain rodents by the neurotoxin MPTP. In this study, we aimed to test the hypothesis that there are factors in the VTA that are potentially neuroprotective against MPTP and that these factors change over time. We have found a differential transcriptional response within the cells of the SN and VTA to sustained exposure to a low dose of MPTP. Specifically, the VTA has increased expression of 148 genes as an early response to MPTP and 113 genes as a late response to MPTP toxicity. This response encompasses many areas of cellular function, including protein regulation (Phf6) and ion/metal regulation (PANK2, Car4). Notably, these responses were largely absent from the cells of the SN. Our data show a clear dynamic response in maintaining the homeostasis and viability of the neurons in the VTA that is lacking in the SN after neurotoxin challenge. We used microarrays to analyze the differential response of the substantia nigra (SN) and ventral tegmental area (VTA) to a chronic low dose of the neurotoxin MPTP. Transgenic hTH-GFP mice were treated with MPTP (4mg/kg) for either 2 or 10 days. Control mice were given an equal volume of saline for 10 days. Dopamine neurons from the substantia nigra and ventral tegmental areas of control and MPTP treated animals were laser captured. The RNA was isolated and processed for microarray hybridization. Each group had three biological replicates, for a total of 18 samples. Three each in the following: Control SN, Control VTA, 2 day MPTP SN, 2 day MPTP VTA, 10 day MPTP SN, 10 day MPTP VTA. Samples were log2 transformed and RMA normalized using Agilent Genespring 10.0 GX.

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Defining specific cell states of MPTP-induced Parkinson's disease by single-nucleus RNA sequencing

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