Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing Mice
Parkinson’s disease (PD) is a progressive neurodegenerative disorder with motor symptoms and a plethora of non-motor and neuropsychiatric features that accompany the disease from prodromal to advanced stages. While several genetic defects have been identified in familial forms of PD, the predominanc...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2018.01033/full |
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| author | Zinah Wassouf Thomas Hentrich Nicolas Casadei Mirko Jaumann Marlies Knipper Olaf Riess Julia M. Schulze-Hentrich |
| author_facet | Zinah Wassouf Thomas Hentrich Nicolas Casadei Mirko Jaumann Marlies Knipper Olaf Riess Julia M. Schulze-Hentrich |
| author_sort | Zinah Wassouf |
| collection | DOAJ |
| description | Parkinson’s disease (PD) is a progressive neurodegenerative disorder with motor symptoms and a plethora of non-motor and neuropsychiatric features that accompany the disease from prodromal to advanced stages. While several genetic defects have been identified in familial forms of PD, the predominance of cases are sporadic and result from a complex interplay of genetic and non-genetic factors. Clinical evidence, moreover, indicates a role of environmental stress in PD, supported by analogies between stress-induced pathological consequences and neuronal deterioration observed in PD. From this perspective, we set out to investigate the effects of chronic stress exposure in the context of PD by using a genetic mouse model that overexpresses human wildtype SNCA. Mimicking chronic stress was achieved by adapting a chronic unpredictable mild stress protocol (CUMS) comprising eight different stressors that were applied randomly over a period of eight weeks starting at an age of four months. A distinctive stress response with an impact on anxiety-related behavior was observed upon SNCA overexpression and CUMS exposure. SNCA-overexpressing mice showed prolonged elevation of cortisol metabolites during CUMS exposure, altered anxiety-related traits, and declined motor skills surfacing with advanced age. To relate our phenotypic observations to molecular events, we profiled the striatal and hippocampal transcriptome and used a 2 × 2 factorial design opposing genotype and environment to determine differentially expressed genes. Disturbed striatal gene expression and minor hippocampal gene expression changes were observed in SNCA-overexpressing mice at six months of age. Irrespective of the CUMS-exposure, genes attributed to the terms neuroinflammation, Parkinson’s signaling, and plasticity of synapses were altered in the striatum of SNCA-overexpressing mice. |
| first_indexed | 2024-12-19T19:52:17Z |
| format | Article |
| id | doaj.art-23308d8322834211af0762c65169f1c8 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-19T19:52:17Z |
| publishDate | 2019-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-23308d8322834211af0762c65169f1c82022-12-21T20:07:57ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-01-011210.3389/fnins.2018.01033435940Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing MiceZinah Wassouf0Thomas Hentrich1Nicolas Casadei2Mirko Jaumann3Marlies Knipper4Olaf Riess5Julia M. Schulze-Hentrich6Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, GermanyMolecular Physiology of Hearing, Department of Otolaryngology, Tübingen Hearing Research Centre, University of Tübingen, Tübingen, GermanyMolecular Physiology of Hearing, Department of Otolaryngology, Tübingen Hearing Research Centre, University of Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, GermanyParkinson’s disease (PD) is a progressive neurodegenerative disorder with motor symptoms and a plethora of non-motor and neuropsychiatric features that accompany the disease from prodromal to advanced stages. While several genetic defects have been identified in familial forms of PD, the predominance of cases are sporadic and result from a complex interplay of genetic and non-genetic factors. Clinical evidence, moreover, indicates a role of environmental stress in PD, supported by analogies between stress-induced pathological consequences and neuronal deterioration observed in PD. From this perspective, we set out to investigate the effects of chronic stress exposure in the context of PD by using a genetic mouse model that overexpresses human wildtype SNCA. Mimicking chronic stress was achieved by adapting a chronic unpredictable mild stress protocol (CUMS) comprising eight different stressors that were applied randomly over a period of eight weeks starting at an age of four months. A distinctive stress response with an impact on anxiety-related behavior was observed upon SNCA overexpression and CUMS exposure. SNCA-overexpressing mice showed prolonged elevation of cortisol metabolites during CUMS exposure, altered anxiety-related traits, and declined motor skills surfacing with advanced age. To relate our phenotypic observations to molecular events, we profiled the striatal and hippocampal transcriptome and used a 2 × 2 factorial design opposing genotype and environment to determine differentially expressed genes. Disturbed striatal gene expression and minor hippocampal gene expression changes were observed in SNCA-overexpressing mice at six months of age. Irrespective of the CUMS-exposure, genes attributed to the terms neuroinflammation, Parkinson’s signaling, and plasticity of synapses were altered in the striatum of SNCA-overexpressing mice.https://www.frontiersin.org/article/10.3389/fnins.2018.01033/fullalpha-synucleinchronic unpredictable mild stressParkinson’s diseasetranscriptomepsychiatric-related behavior |
| spellingShingle | Zinah Wassouf Thomas Hentrich Nicolas Casadei Mirko Jaumann Marlies Knipper Olaf Riess Julia M. Schulze-Hentrich Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing Mice Frontiers in Neuroscience alpha-synuclein chronic unpredictable mild stress Parkinson’s disease transcriptome psychiatric-related behavior |
| title | Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing Mice |
| title_full | Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing Mice |
| title_fullStr | Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing Mice |
| title_full_unstemmed | Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing Mice |
| title_short | Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing Mice |
| title_sort | distinct stress response and altered striatal transcriptome in alpha synuclein overexpressing mice |
| topic | alpha-synuclein chronic unpredictable mild stress Parkinson’s disease transcriptome psychiatric-related behavior |
| url | https://www.frontiersin.org/article/10.3389/fnins.2018.01033/full |
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