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Transcriptional profiling of myeloid cells (CD11b) and astrocytes (ACSA2) from the striatum and the midbrain of control and parkinsonian animals in the MPTP mouse model

ABSTRACT: Neuroinflammation is a common hallmark of neurodegenerative diseases such as Parkinson’s disease (PD). Here, we questioned about the activation state of glial cells along the degeneration process of dopaminergic terminals in the striatum and loss of neuronal cell bodies in the midbrain. We hypothesized that MPTP administration pattern would produce different inflammatory responses that could modify the course of nigrostriatal degeneration. To reproduce the dopaminergic impairment in a PD experimental mouse model, we used two different MPTP-administration patterns: subacute (sMPTP) and chronic (cMPTP). Bulk RNA sequencing of purified midbrain microglia/myeloid cells of sMPTP mice showed an anti-inflammatory phenotype, while midbrain microglia/myeloid cells of cMPTP mice showed a pro-inflammatory and phagocytic phenotype. Midbrain astrocytes presented a phagocytic phenotype in sMPTP mice. In the striatum, microglia presented a continuous pro-inflammatory state in sMPTP and cMPTP conditions. In this region, astrocytes presented a remarkable activated and phagocytic state in sMPTP mice which was attenuated with the chronicity of MPTP administration.

ORGANISM(S): Mus musculus

PROVIDER: GSE244652 | GEO | 2024/04/08

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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Transcriptional profiling of myeloid cells (CD11b) and astrocytes (ACSA2) from the striatum and the midbrain of control and parkinsonian animals in the MPTP mouse model

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