Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice
<p dir="ltr">Approximately 90% of alpha-synuclein (α-Synuclein) deposited in Lewy bodies is phosphorylated at serine 129 suggesting that the accumulation of phosphorylated α-Synuclein is critical in the pathogenesis of Parkinson’s disease. However, in vivo experiments addressing the...
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| مؤلفون آخرون: | , , , , , , , , |
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2017
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| _version_ | 1864513556580401152 |
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| author | Mantia Karampetsou (8737815) |
| author2 | Mustafa T. Ardah (4858657) Maria Semitekolou (2938959) Alexia Polissidis (3040905) Martina Samiotaki (438647) Maria Kalomoiri (16874580) Nour Majbour (3528548) Georgina Xanthou (8344188) Omar M. A. El-Agnaf (8809331) Kostas Vekrellis (214282) |
| author2_role | author author author author author author author author author |
| author_facet | Mantia Karampetsou (8737815) Mustafa T. Ardah (4858657) Maria Semitekolou (2938959) Alexia Polissidis (3040905) Martina Samiotaki (438647) Maria Kalomoiri (16874580) Nour Majbour (3528548) Georgina Xanthou (8344188) Omar M. A. El-Agnaf (8809331) Kostas Vekrellis (214282) |
| author_role | author |
| dc.creator.none.fl_str_mv | Mantia Karampetsou (8737815) Mustafa T. Ardah (4858657) Maria Semitekolou (2938959) Alexia Polissidis (3040905) Martina Samiotaki (438647) Maria Kalomoiri (16874580) Nour Majbour (3528548) Georgina Xanthou (8344188) Omar M. A. El-Agnaf (8809331) Kostas Vekrellis (214282) |
| dc.date.none.fl_str_mv | 2017-11-28T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41598-017-15813-8 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Phosphorylated_exogenous_alpha-synuclein_fibrils_exacerbate_pathology_and_induce_neuronal_dysfunction_in_mice/27088018 |
| 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 Neurosciences Alpha-synuclein (α-Synuclein) Parkinson’s disease Phosphorylation Lewy bodies Stereotaxic injections Neurodegeneration |
| dc.title.none.fl_str_mv | Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Approximately 90% of alpha-synuclein (α-Synuclein) deposited in Lewy bodies is phosphorylated at serine 129 suggesting that the accumulation of phosphorylated α-Synuclein is critical in the pathogenesis of Parkinson’s disease. However, in vivo experiments addressing the role of phosphorylated α-Synuclein in the progression of Parkinson’s disease have produced equivocal data. To clarify a role of Ser129 phosphorylation of α-Synuclein in pathology progression we performed stereotaxic injections targeting the mouse striatum with three fibrilar α-Synuclein types: wt-fibrils, phosphorylated S129 fibrils and, phosphorylation incompetent, S129A fibrils. Brain inoculation of all three fibrilar types caused seeding of the endogenous α-Synuclein. However, phosphorylated fibrils triggered the formation of more α-Synuclein inclusions in the Substantia Nigra pars compacta (SNpc), exacerbated pathology in the cortex and caused dopaminergic neuronal loss and fine motor impairment as early as 60 days post injection. Phosphorylated fibril injections also induced early changes in the innate immune response including alterations in macrophage recruitment and IL-10 release. Our study further shows that S129 phosphorylation facilitated α-Synuclein fibril uptake by neurons. Our results highlight the role of phosphorylated fibrilar α-Synuclein in pathology progression in vivo and suggest that targeting phosphorylated α-Synuclein assemblies might be important for delaying inclusion formation.</p><h2>Other Information</h2><p dir="ltr">Published in: Scientific Reports<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/10.1038/s41598-017-15813-8" target="_blank">https://dx.doi.org/10.1038/s41598-017-15813-8</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_93ba161f3939c51b32dd3b2db30d21d2 |
| identifier_str_mv | 10.1038/s41598-017-15813-8 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/27088018 |
| publishDate | 2017 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in miceMantia Karampetsou (8737815)Mustafa T. Ardah (4858657)Maria Semitekolou (2938959)Alexia Polissidis (3040905)Martina Samiotaki (438647)Maria Kalomoiri (16874580)Nour Majbour (3528548)Georgina Xanthou (8344188)Omar M. A. El-Agnaf (8809331)Kostas Vekrellis (214282)Biomedical and clinical sciencesNeurosciencesAlpha-synuclein (α-Synuclein)Parkinson’s diseasePhosphorylationLewy bodiesStereotaxic injectionsNeurodegeneration<p dir="ltr">Approximately 90% of alpha-synuclein (α-Synuclein) deposited in Lewy bodies is phosphorylated at serine 129 suggesting that the accumulation of phosphorylated α-Synuclein is critical in the pathogenesis of Parkinson’s disease. However, in vivo experiments addressing the role of phosphorylated α-Synuclein in the progression of Parkinson’s disease have produced equivocal data. To clarify a role of Ser129 phosphorylation of α-Synuclein in pathology progression we performed stereotaxic injections targeting the mouse striatum with three fibrilar α-Synuclein types: wt-fibrils, phosphorylated S129 fibrils and, phosphorylation incompetent, S129A fibrils. Brain inoculation of all three fibrilar types caused seeding of the endogenous α-Synuclein. However, phosphorylated fibrils triggered the formation of more α-Synuclein inclusions in the Substantia Nigra pars compacta (SNpc), exacerbated pathology in the cortex and caused dopaminergic neuronal loss and fine motor impairment as early as 60 days post injection. Phosphorylated fibril injections also induced early changes in the innate immune response including alterations in macrophage recruitment and IL-10 release. Our study further shows that S129 phosphorylation facilitated α-Synuclein fibril uptake by neurons. Our results highlight the role of phosphorylated fibrilar α-Synuclein in pathology progression in vivo and suggest that targeting phosphorylated α-Synuclein assemblies might be important for delaying inclusion formation.</p><h2>Other Information</h2><p dir="ltr">Published in: Scientific Reports<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/10.1038/s41598-017-15813-8" target="_blank">https://dx.doi.org/10.1038/s41598-017-15813-8</a></p>2017-11-28T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41598-017-15813-8https://figshare.com/articles/journal_contribution/Phosphorylated_exogenous_alpha-synuclein_fibrils_exacerbate_pathology_and_induce_neuronal_dysfunction_in_mice/27088018CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/270880182017-11-28T03:00:00Z |
| spellingShingle | Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice Mantia Karampetsou (8737815) Biomedical and clinical sciences Neurosciences Alpha-synuclein (α-Synuclein) Parkinson’s disease Phosphorylation Lewy bodies Stereotaxic injections Neurodegeneration |
| status_str | publishedVersion |
| title | Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice |
| title_full | Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice |
| title_fullStr | Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice |
| title_full_unstemmed | Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice |
| title_short | Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice |
| title_sort | Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice |
| topic | Biomedical and clinical sciences Neurosciences Alpha-synuclein (α-Synuclein) Parkinson’s disease Phosphorylation Lewy bodies Stereotaxic injections Neurodegeneration |