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Updated: Jul 8, 2025
Analyzing the Parkinson's Disease Mouse Model Induced by Adeno-associated Viral Vectors Encoding Human α-Synuclein
Published on: July 29, 2022
Region-specific changes in gene expression are associated with cognitive deficits in the alpha-synuclein-induced
Maria Francesca Manchinu1, Mauro Pala1, Maria Francesca Palmas2
1National Research Council, Biomedical and Genetic Research Institute, 09040 Cagliari, Italy.
Abstract:
Mild cognitive impairment (MCI) is a common trait of Parkinson's disease (PD), often associated with early motor deficits, eventually evolving to PD with dementia in later disease stages. The neuropathological substrate of MCI is poorly understood, which weakens the development and administration of proper therapies. In an α-synuclein (αSyn)-based model of PD featuring early motor and cognitive impairments, we investigated the transcriptome profile of brain regions involved in PD with cognitive deficits, via a transcriptomic analysis based on RNA sequencing (RNA-seq) technology. Rats infused in the substantia nigra with human α-synuclein oligomers (H-SynOs) developed mild cognitive deficits after three months, as measured by the two-trial recognition test in a Y-maze and the novel object recognition test. RNA-seq analysis showed that 17,436 genes were expressed in the anterior cingulate cortex (ACC) and 17,216 genes in the hippocampus (HC). In the ACC, 51 genes were differentially expressed between vehicle and H-αSynOs treated samples, which showed N= 21 upregulated and N = 30 downregulated genes. In the HC, 104 genes were differentially expressed, the majority of them not overlapping with DEGs in the ACC, with N = 41 upregulated and N = 63 downregulated in H-αSynOs-treated samples. The Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis, followed by the protein-protein interaction (PPI) network inspection of DEGs, revealed that in the ACC most enriched terms were related with immune functions, specifically with antigen processing/presentation via the major histocompatibility complex (MHC) class II and phagocytosis via CD68, supporting a role for dysregulated immune responses in early PD cognitive dysfunction. Immunofluorescence analysis confirmed the decreased expression of CD68 within microglial cells. In contrast, the most significantly enriched terms in the HC were mainly involved in mitochondrial homeostasis, potassium voltage-gated channel, cytoskeleton and fiber organisation, suggesting that the gene expression in the neuronal population was mostly affected in this region in early disease stages. Altogether results show that H-αSynOs trigger a region-specific dysregulation of gene expression in ACC and HC, providing a pathological substrate for MCI associated with early PD.
Insights
This study reveals region-specific gene expression changes in the brain linked to mild cognitive impairment in Parkinson's disease (PD). Alpha-synuclein oligomers trigger immune responses in the anterior cingulate cortex and mitochondrial issues in the hippocampus, offering insights into PD dementia.
Area of Science:
- Neuroscience
- Genomics
- Pathology
Background:
- Mild cognitive impairment (MCI) is a frequent early symptom of Parkinson's disease (PD), often preceding or accompanying motor deficits.
- The underlying neuropathological mechanisms of MCI in PD remain poorly understood, hindering effective therapeutic development.
- Alpha-synuclein (αSyn) aggregation is a hallmark of PD, and its role in cognitive decline is an active area of research.
Purpose of the Study:
- To investigate the transcriptome profile of brain regions implicated in cognitive deficits in an αSyn-based rat model of Parkinson's disease.
- To identify differentially expressed genes (DEGs) and associated biological pathways in the anterior cingulate cortex (ACC) and hippocampus (HC) during early stages of PD-related cognitive impairment.
- To elucidate the neuropathological substrate of MCI in PD by examining region-specific gene expression changes.
Main Methods:
- Utilized an α-synuclein (αSyn)-based rat model of Parkinson's disease (PD) by infusing human α-synuclein oligomers (H-SynOs) into the substantia nigra.
- Assessed mild cognitive deficits using behavioral tests, including the two-trial recognition test in a Y-maze and the novel object recognition test.
- Performed RNA sequencing (RNA-seq) on the anterior cingulate cortex (ACC) and hippocampus (HC) to analyze gene expression profiles.
- Conducted Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analysis, and protein-protein interaction (PPI) network analysis on differentially expressed genes (DEGs).
- Confirmed findings using immunofluorescence analysis to assess CD68 expression in microglial cells.
Main Results:
- Rats infused with H-SynOs exhibited mild cognitive deficits three months post-infusion.
- RNA-seq analysis revealed significant differential gene expression in both the ACC (51 DEGs) and HC (104 DEGs) compared to vehicle-treated controls.
- In the ACC, enriched terms pointed towards immune system dysregulation, including antigen processing and presentation via MHC class II and phagocytosis (CD68), with decreased CD68 expression observed in microglia.
- In the HC, enriched terms were primarily associated with mitochondrial homeostasis, potassium channels, and cytoskeleton organization, suggesting neuronal population impact.
- DEG profiles in the ACC and HC showed minimal overlap, indicating region-specific molecular responses.
Conclusions:
- Human α-synuclein oligomers induce region-specific transcriptomic alterations in the ACC and HC, contributing to mild cognitive impairment in a PD model.
- The findings suggest a role for dysregulated immune responses in the ACC and mitochondrial dysfunction in the HC in the neuropathology of early PD-related cognitive deficits.
- This study provides a molecular basis for understanding MCI in Parkinson's disease and highlights potential therapeutic targets.
