Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils
Abstract Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-synuclein (α-syn) preformed fibril (PFF) model induce...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-023-00620-y |
| _version_ | 1797363518870126592 |
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| author | Joseph R. Patterson Joseph Kochmanski Anna C. Stoll Michael Kubik Christopher J. Kemp Megan F. Duffy Kajene Thompson Jacob W. Howe Allyson Cole-Strauss Nathan C. Kuhn Kathryn M. Miller Seth Nelson Christopher U. Onyekpe John S. Beck Scott E. Counts Alison I. Bernstein Kathy Steece-Collier Kelvin C. Luk Caryl E. Sortwell |
| author_facet | Joseph R. Patterson Joseph Kochmanski Anna C. Stoll Michael Kubik Christopher J. Kemp Megan F. Duffy Kajene Thompson Jacob W. Howe Allyson Cole-Strauss Nathan C. Kuhn Kathryn M. Miller Seth Nelson Christopher U. Onyekpe John S. Beck Scott E. Counts Alison I. Bernstein Kathy Steece-Collier Kelvin C. Luk Caryl E. Sortwell |
| author_sort | Joseph R. Patterson |
| collection | DOAJ |
| description | Abstract Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-synuclein (α-syn) preformed fibril (PFF) model induces synchronized synucleinopathy that recapitulates the pathological features of Parkinson’s disease (PD) and can be used to study synucleinopathy progression. In this model, phosphorylated α-syn (pSyn) inclusion-containing neurons and reactive microglia (major histocompatibility complex-II immunoreactive) peak in the substantia nigra pars compacta (SNpc) months before appreciable neurodegeneration. However, it remains unclear which specific genes are driving these phenotypic changes. To identify transcriptional changes associated with early synucleinopathy, we used laser capture microdissection of the SNpc paired with RNA sequencing (RNASeq). Precision collection of the SNpc allowed for the assessment of differential transcript expression in the nigral dopamine neurons and proximal glia. Transcripts upregulated in early synucleinopathy were mainly associated with an immune response, whereas transcripts downregulated were associated with neurotransmission and the dopamine pathway. A subset of 29 transcripts associated with neurotransmission/vesicular release and the dopamine pathway were verified in a separate cohort of males and females to confirm reproducibility. Within this subset, fluorescent in situ hybridization (FISH) was used to localize decreases in the Syt1 and Slc6a3 transcripts to pSyn inclusion-containing neurons. Identification of transcriptional changes in early synucleinopathy provides insight into the molecular mechanisms driving neurodegeneration. |
| first_indexed | 2024-03-08T16:22:30Z |
| format | Article |
| id | doaj.art-8bde4016617e4debb09532f2fc4a2cc0 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-08T16:22:30Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-8bde4016617e4debb09532f2fc4a2cc02024-01-07T12:17:09ZengNature Portfolionpj Parkinson's Disease2373-80572024-01-0110111710.1038/s41531-023-00620-yTranscriptomic profiling of early synucleinopathy in rats induced with preformed fibrilsJoseph R. Patterson0Joseph Kochmanski1Anna C. Stoll2Michael Kubik3Christopher J. Kemp4Megan F. Duffy5Kajene Thompson6Jacob W. Howe7Allyson Cole-Strauss8Nathan C. Kuhn9Kathryn M. Miller10Seth Nelson11Christopher U. Onyekpe12John S. Beck13Scott E. Counts14Alison I. Bernstein15Kathy Steece-Collier16Kelvin C. Luk17Caryl E. Sortwell18Department of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityDepartment of Translational Science and Molecular Medicine, Michigan State UniversityCenter for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of MedicineDepartment of Translational Science and Molecular Medicine, Michigan State UniversityAbstract Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-synuclein (α-syn) preformed fibril (PFF) model induces synchronized synucleinopathy that recapitulates the pathological features of Parkinson’s disease (PD) and can be used to study synucleinopathy progression. In this model, phosphorylated α-syn (pSyn) inclusion-containing neurons and reactive microglia (major histocompatibility complex-II immunoreactive) peak in the substantia nigra pars compacta (SNpc) months before appreciable neurodegeneration. However, it remains unclear which specific genes are driving these phenotypic changes. To identify transcriptional changes associated with early synucleinopathy, we used laser capture microdissection of the SNpc paired with RNA sequencing (RNASeq). Precision collection of the SNpc allowed for the assessment of differential transcript expression in the nigral dopamine neurons and proximal glia. Transcripts upregulated in early synucleinopathy were mainly associated with an immune response, whereas transcripts downregulated were associated with neurotransmission and the dopamine pathway. A subset of 29 transcripts associated with neurotransmission/vesicular release and the dopamine pathway were verified in a separate cohort of males and females to confirm reproducibility. Within this subset, fluorescent in situ hybridization (FISH) was used to localize decreases in the Syt1 and Slc6a3 transcripts to pSyn inclusion-containing neurons. Identification of transcriptional changes in early synucleinopathy provides insight into the molecular mechanisms driving neurodegeneration.https://doi.org/10.1038/s41531-023-00620-y |
| spellingShingle | Joseph R. Patterson Joseph Kochmanski Anna C. Stoll Michael Kubik Christopher J. Kemp Megan F. Duffy Kajene Thompson Jacob W. Howe Allyson Cole-Strauss Nathan C. Kuhn Kathryn M. Miller Seth Nelson Christopher U. Onyekpe John S. Beck Scott E. Counts Alison I. Bernstein Kathy Steece-Collier Kelvin C. Luk Caryl E. Sortwell Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils npj Parkinson's Disease |
| title | Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils |
| title_full | Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils |
| title_fullStr | Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils |
| title_full_unstemmed | Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils |
| title_short | Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils |
| title_sort | transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils |
| url | https://doi.org/10.1038/s41531-023-00620-y |
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