Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains
<h3>Background</h3><p dir="ltr">Alpha-synuclein (α-syn) aggregation into proteinaceous intraneuronal inclusions, called Lewy bodies (LBs), is the neuropathological hallmark of Parkinson’s disease (PD) and related synucleinopathies. However, the exact role of α-syn inclusi...
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2023
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| _version_ | 1864513520759996416 |
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| author | Morgan Bérard (12219298) |
| author2 | Laura Martínez-Drudis (17460758) Razan Sheta (3825544) Omar M. A. El-Agnaf (8809331) Abid Oueslati (816135) |
| author2_role | author author author author |
| author_facet | Morgan Bérard (12219298) Laura Martínez-Drudis (17460758) Razan Sheta (3825544) Omar M. A. El-Agnaf (8809331) Abid Oueslati (816135) |
| author_role | author |
| dc.creator.none.fl_str_mv | Morgan Bérard (12219298) Laura Martínez-Drudis (17460758) Razan Sheta (3825544) Omar M. A. El-Agnaf (8809331) Abid Oueslati (816135) |
| dc.date.none.fl_str_mv | 2023-11-27T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1186/s13024-023-00683-8 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Non-invasive_systemic_viral_delivery_of_human_alpha-synuclein_mimics_selective_and_progressive_neuropathology_of_Parkinson_s_disease_in_rodent_brains/26776462 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Neurosciences Alpha-synuclein Adeno-associated virus AAV-PHP.eB Neurodegeneration Parkinson’s Disease Animal model Systemic delivery . PD-like symptoms Genetic model of PD Protein aggregation |
| dc.title.none.fl_str_mv | Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">Alpha-synuclein (α-syn) aggregation into proteinaceous intraneuronal inclusions, called Lewy bodies (LBs), is the neuropathological hallmark of Parkinson’s disease (PD) and related synucleinopathies. However, the exact role of α-syn inclusions in PD pathogenesis remains elusive. This lack of knowledge is mainly due to the absence of optimal α-syn-based animal models that recapitulate the different stages of neurodegeneration.</p><h3>Methods</h3><p dir="ltr">Here we describe a novel approach for a systemic delivery of viral particles carrying human α-syn allowing for a large-scale overexpression of this protein in the mouse brain. This approach is based on the use of a new generation of adeno-associated virus (AAV), AAV-PHP.eB, with an increased capacity to cross the blood-brain barrier, thus offering a viable tool for a non-invasive and large-scale gene delivery in the central nervous system.</p><h3>Results</h3><p dir="ltr">Using this model, we report that widespread overexpression of human α-syn induced selective degeneration of dopaminergic (DA) neurons, an exacerbated neuroinflammatory response in the substantia nigra and a progressive manifestation of PD-like motor impairments. Interestingly, biochemical analysis revealed the presence of insoluble α-syn oligomers in the midbrain. Together, our data demonstrate that a single non-invasive systemic delivery of viral particles overexpressing α-syn prompted selective and progressive neuropathology resembling the early stages of PD.</p><h3>Conclusions</h3><p dir="ltr">Our new in vivo model represents a valuable tool to study the role of α-syn in PD pathogenesis and in the selective vulnerability of nigral DA neurons; and offers the opportunity to test new strategies targeting α-syn toxicity for the development of disease-modifying therapies for PD and related disorders.</p><h2>Other Information</h2><p dir="ltr">Published in: Molecular Neurodegeneration<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s13024-023-00683-8" target="_blank">https://dx.doi.org/10.1186/s13024-023-00683-8</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_a3fec7e95d3e0ea66ac8848d97653d5c |
| identifier_str_mv | 10.1186/s13024-023-00683-8 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26776462 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brainsMorgan Bérard (12219298)Laura Martínez-Drudis (17460758)Razan Sheta (3825544)Omar M. A. El-Agnaf (8809331)Abid Oueslati (816135)Biomedical and clinical sciencesClinical sciencesNeurosciencesAlpha-synucleinAdeno-associated virusAAV-PHP.eBNeurodegeneration Parkinson’sDisease Animal modelSystemic delivery .PD-like symptomsGenetic model of PDProtein aggregation<h3>Background</h3><p dir="ltr">Alpha-synuclein (α-syn) aggregation into proteinaceous intraneuronal inclusions, called Lewy bodies (LBs), is the neuropathological hallmark of Parkinson’s disease (PD) and related synucleinopathies. However, the exact role of α-syn inclusions in PD pathogenesis remains elusive. This lack of knowledge is mainly due to the absence of optimal α-syn-based animal models that recapitulate the different stages of neurodegeneration.</p><h3>Methods</h3><p dir="ltr">Here we describe a novel approach for a systemic delivery of viral particles carrying human α-syn allowing for a large-scale overexpression of this protein in the mouse brain. This approach is based on the use of a new generation of adeno-associated virus (AAV), AAV-PHP.eB, with an increased capacity to cross the blood-brain barrier, thus offering a viable tool for a non-invasive and large-scale gene delivery in the central nervous system.</p><h3>Results</h3><p dir="ltr">Using this model, we report that widespread overexpression of human α-syn induced selective degeneration of dopaminergic (DA) neurons, an exacerbated neuroinflammatory response in the substantia nigra and a progressive manifestation of PD-like motor impairments. Interestingly, biochemical analysis revealed the presence of insoluble α-syn oligomers in the midbrain. Together, our data demonstrate that a single non-invasive systemic delivery of viral particles overexpressing α-syn prompted selective and progressive neuropathology resembling the early stages of PD.</p><h3>Conclusions</h3><p dir="ltr">Our new in vivo model represents a valuable tool to study the role of α-syn in PD pathogenesis and in the selective vulnerability of nigral DA neurons; and offers the opportunity to test new strategies targeting α-syn toxicity for the development of disease-modifying therapies for PD and related disorders.</p><h2>Other Information</h2><p dir="ltr">Published in: Molecular Neurodegeneration<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s13024-023-00683-8" target="_blank">https://dx.doi.org/10.1186/s13024-023-00683-8</a></p>2023-11-27T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s13024-023-00683-8https://figshare.com/articles/journal_contribution/Non-invasive_systemic_viral_delivery_of_human_alpha-synuclein_mimics_selective_and_progressive_neuropathology_of_Parkinson_s_disease_in_rodent_brains/26776462CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/267764622023-11-27T09:00:00Z |
| spellingShingle | Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains Morgan Bérard (12219298) Biomedical and clinical sciences Clinical sciences Neurosciences Alpha-synuclein Adeno-associated virus AAV-PHP.eB Neurodegeneration Parkinson’s Disease Animal model Systemic delivery . PD-like symptoms Genetic model of PD Protein aggregation |
| status_str | publishedVersion |
| title | Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains |
| title_full | Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains |
| title_fullStr | Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains |
| title_full_unstemmed | Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains |
| title_short | Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains |
| title_sort | Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains |
| topic | Biomedical and clinical sciences Clinical sciences Neurosciences Alpha-synuclein Adeno-associated virus AAV-PHP.eB Neurodegeneration Parkinson’s Disease Animal model Systemic delivery . PD-like symptoms Genetic model of PD Protein aggregation |