Exposure of α-Synuclein Aggregates to Organotypic Slice Cultures Recapitulates Key Molecular Features of Parkinson's Disease
The accumulation of proteinaceous deposits comprised largely of the α-synuclein protein is one of the main hallmarks of Parkinson's disease (PD) and related synucleinopathies. Their progressive development coincides with site-specific phosphorylation, oxidative stress and eventually, compromise...
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2022.826102/full |
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| author | Serge Moudio Fredrik Rodin Nazira Jamal Albargothy Urban Karlsson Juan F. Reyes Martin Hallbeck |
| author_facet | Serge Moudio Fredrik Rodin Nazira Jamal Albargothy Urban Karlsson Juan F. Reyes Martin Hallbeck |
| author_sort | Serge Moudio |
| collection | DOAJ |
| description | The accumulation of proteinaceous deposits comprised largely of the α-synuclein protein is one of the main hallmarks of Parkinson's disease (PD) and related synucleinopathies. Their progressive development coincides with site-specific phosphorylation, oxidative stress and eventually, compromised neuronal function. However, modeling protein aggregate formation in animal or in vitro models has proven notably difficult. Here, we took advantage of a preclinical organotypic brain slice culture model to study α-synuclein aggregate formation ex vivo. We monitored the progressive and gradual changes induced by α-synuclein such as cellular toxicity, autophagy activation, mitochondrial dysfunction, cellular death as well as α-synuclein modification including site-specific phosphorylation. Our results demonstrate that organotypic brain slice cultures can be cultured for long periods of time and when cultured in the presence of aggregated α-synuclein, the molecular features of PD are recapitulated. Taken together, this ex vivo model allows for detailed modeling of the molecular features of PD, thus enabling studies on the cumulative effects of α-synuclein in a complex environment. This provides a platform to screen potential disease-modifying therapeutic candidates aimed at impeding α-synuclein aggregation and/or cellular transmission. Moreover, this model provides a robust replacement for in vivo studies that do not include behavioral experiments, thus providing a way to reduce the number of animals used in an accelerated timescale. |
| first_indexed | 2024-12-24T03:29:34Z |
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| id | doaj.art-9f67a8c12f044408a9929d0843d9ad2b |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-24T03:29:34Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-9f67a8c12f044408a9929d0843d9ad2b2022-12-21T17:17:15ZengFrontiers Media S.A.Frontiers in Neurology1664-22952022-02-011310.3389/fneur.2022.826102826102Exposure of α-Synuclein Aggregates to Organotypic Slice Cultures Recapitulates Key Molecular Features of Parkinson's DiseaseSerge Moudio0Fredrik Rodin1Nazira Jamal Albargothy2Urban Karlsson3Juan F. Reyes4Martin Hallbeck5Department of Clinical Pathology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Clinical Pathology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Clinical Pathology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Clinical Pathology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Clinical Pathology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenThe accumulation of proteinaceous deposits comprised largely of the α-synuclein protein is one of the main hallmarks of Parkinson's disease (PD) and related synucleinopathies. Their progressive development coincides with site-specific phosphorylation, oxidative stress and eventually, compromised neuronal function. However, modeling protein aggregate formation in animal or in vitro models has proven notably difficult. Here, we took advantage of a preclinical organotypic brain slice culture model to study α-synuclein aggregate formation ex vivo. We monitored the progressive and gradual changes induced by α-synuclein such as cellular toxicity, autophagy activation, mitochondrial dysfunction, cellular death as well as α-synuclein modification including site-specific phosphorylation. Our results demonstrate that organotypic brain slice cultures can be cultured for long periods of time and when cultured in the presence of aggregated α-synuclein, the molecular features of PD are recapitulated. Taken together, this ex vivo model allows for detailed modeling of the molecular features of PD, thus enabling studies on the cumulative effects of α-synuclein in a complex environment. This provides a platform to screen potential disease-modifying therapeutic candidates aimed at impeding α-synuclein aggregation and/or cellular transmission. Moreover, this model provides a robust replacement for in vivo studies that do not include behavioral experiments, thus providing a way to reduce the number of animals used in an accelerated timescale.https://www.frontiersin.org/articles/10.3389/fneur.2022.826102/fullParkinson's diseaseα-synucleinPFForganotypic slice culturesautophagy3R |
| spellingShingle | Serge Moudio Fredrik Rodin Nazira Jamal Albargothy Urban Karlsson Juan F. Reyes Martin Hallbeck Exposure of α-Synuclein Aggregates to Organotypic Slice Cultures Recapitulates Key Molecular Features of Parkinson's Disease Frontiers in Neurology Parkinson's disease α-synuclein PFF organotypic slice cultures autophagy 3R |
| title | Exposure of α-Synuclein Aggregates to Organotypic Slice Cultures Recapitulates Key Molecular Features of Parkinson's Disease |
| title_full | Exposure of α-Synuclein Aggregates to Organotypic Slice Cultures Recapitulates Key Molecular Features of Parkinson's Disease |
| title_fullStr | Exposure of α-Synuclein Aggregates to Organotypic Slice Cultures Recapitulates Key Molecular Features of Parkinson's Disease |
| title_full_unstemmed | Exposure of α-Synuclein Aggregates to Organotypic Slice Cultures Recapitulates Key Molecular Features of Parkinson's Disease |
| title_short | Exposure of α-Synuclein Aggregates to Organotypic Slice Cultures Recapitulates Key Molecular Features of Parkinson's Disease |
| title_sort | exposure of α synuclein aggregates to organotypic slice cultures recapitulates key molecular features of parkinson s disease |
| topic | Parkinson's disease α-synuclein PFF organotypic slice cultures autophagy 3R |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2022.826102/full |
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