Intrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity
Abstract Background Prionoid transmission of α-synuclein (αSyn) aggregates along neuroanatomically connected projections is posited to underlie disease progression in α-synucleinopathies. Here, we specifically wanted to study whether this prionoid progression occurs via direct inter-neuronal transfe...
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| Format: | Article |
| Language: | English |
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BMC
2017-05-01
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| Series: | Molecular Neurodegeneration |
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| Online Access: | http://link.springer.com/article/10.1186/s13024-017-0182-z |
| _version_ | 1818582679867621376 |
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| author | Zachary A. Sorrentino Mieu M.T. Brooks Vincent Hudson Nicola J. Rutherford Todd E. Golde Benoit I. Giasson Paramita Chakrabarty |
| author_facet | Zachary A. Sorrentino Mieu M.T. Brooks Vincent Hudson Nicola J. Rutherford Todd E. Golde Benoit I. Giasson Paramita Chakrabarty |
| author_sort | Zachary A. Sorrentino |
| collection | DOAJ |
| description | Abstract Background Prionoid transmission of α-synuclein (αSyn) aggregates along neuroanatomically connected projections is posited to underlie disease progression in α-synucleinopathies. Here, we specifically wanted to study whether this prionoid progression occurs via direct inter-neuronal transfer and, if so, would intrastriatal injection of αSyn aggregates lead to nigral degeneration. Methods To test prionoid transmission of αSyn aggregates along the nigro-striatal pathway, we injected amyloidogenic αSyn aggregates into two different regions of the striatum of adult human wild type αSyn transgenic mice (Line M20) or non-transgenic (NTG) mice and aged for 4 months. Results M20 mice injected in internal capsule (IC) or caudate putamen (CPu) regions of the striatum showed florid αSyn inclusion pathology distributed throughout the neuraxis, irrespective of anatomic connectivity. These αSyn inclusions were found in different cell types including neurons, astrocytes and even ependymal cells. On the other hand, intra-striatal injection of αSyn fibrils into NTG mice resulted in sparse αSyn pathology, mostly localized in the striatum and entorhinal cortex. Interestingly, NTG mice injected with preformed human αSyn fibrils showed no induction of αSyn inclusion pathology, suggesting the presence of a species barrier for αSyn fibrillar seeds. Modest levels of nigral dopaminergic (DA) neuronal loss was observed exclusively in substantia nigra (SN) of M20 cohorts injected in the IC, even in the absence of frank αSyn inclusions in DA neurons. None of the NTG mice or CPu-injected M20 mice showed DA neurodegeneration. Interestingly, the pattern and distribution of induced αSyn pathology corresponded with neuroinflammation especially in the SN of M20 cohorts. Hypermorphic reactive astrocytes laden with αSyn inclusions were abundantly present in the brains of M20 mice. Conclusions Overall, our findings show that the pattern and extent of dissemination of αSyn pathology does not necessarily follow expected neuroanatomic connectivity. Further, the presence of intra-astrocytic αSyn pathology implies that glial cells participate in αSyn transmission and possibly have a role in non-cell autonomous disease modification. |
| first_indexed | 2024-12-16T07:53:14Z |
| format | Article |
| id | doaj.art-c9e8970133d44a9699752cbf6fee3a81 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-16T07:53:14Z |
| publishDate | 2017-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-c9e8970133d44a9699752cbf6fee3a812022-12-21T22:38:48ZengBMCMolecular Neurodegeneration1750-13262017-05-0112111610.1186/s13024-017-0182-zIntrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivityZachary A. Sorrentino0Mieu M.T. Brooks1Vincent Hudson2Nicola J. Rutherford3Todd E. Golde4Benoit I. Giasson5Paramita Chakrabarty6Department of Neuroscience, University of FloridaDepartment of Neuroscience, University of FloridaDepartment of Neuroscience, University of FloridaDepartment of Neuroscience, University of FloridaDepartment of Neuroscience, University of FloridaDepartment of Neuroscience, University of FloridaDepartment of Neuroscience, University of FloridaAbstract Background Prionoid transmission of α-synuclein (αSyn) aggregates along neuroanatomically connected projections is posited to underlie disease progression in α-synucleinopathies. Here, we specifically wanted to study whether this prionoid progression occurs via direct inter-neuronal transfer and, if so, would intrastriatal injection of αSyn aggregates lead to nigral degeneration. Methods To test prionoid transmission of αSyn aggregates along the nigro-striatal pathway, we injected amyloidogenic αSyn aggregates into two different regions of the striatum of adult human wild type αSyn transgenic mice (Line M20) or non-transgenic (NTG) mice and aged for 4 months. Results M20 mice injected in internal capsule (IC) or caudate putamen (CPu) regions of the striatum showed florid αSyn inclusion pathology distributed throughout the neuraxis, irrespective of anatomic connectivity. These αSyn inclusions were found in different cell types including neurons, astrocytes and even ependymal cells. On the other hand, intra-striatal injection of αSyn fibrils into NTG mice resulted in sparse αSyn pathology, mostly localized in the striatum and entorhinal cortex. Interestingly, NTG mice injected with preformed human αSyn fibrils showed no induction of αSyn inclusion pathology, suggesting the presence of a species barrier for αSyn fibrillar seeds. Modest levels of nigral dopaminergic (DA) neuronal loss was observed exclusively in substantia nigra (SN) of M20 cohorts injected in the IC, even in the absence of frank αSyn inclusions in DA neurons. None of the NTG mice or CPu-injected M20 mice showed DA neurodegeneration. Interestingly, the pattern and distribution of induced αSyn pathology corresponded with neuroinflammation especially in the SN of M20 cohorts. Hypermorphic reactive astrocytes laden with αSyn inclusions were abundantly present in the brains of M20 mice. Conclusions Overall, our findings show that the pattern and extent of dissemination of αSyn pathology does not necessarily follow expected neuroanatomic connectivity. Further, the presence of intra-astrocytic αSyn pathology implies that glial cells participate in αSyn transmission and possibly have a role in non-cell autonomous disease modification.http://link.springer.com/article/10.1186/s13024-017-0182-zα-synucleinAmyloidPrionStriatumDopaminergic NeurodegenerationAstrocyte |
| spellingShingle | Zachary A. Sorrentino Mieu M.T. Brooks Vincent Hudson Nicola J. Rutherford Todd E. Golde Benoit I. Giasson Paramita Chakrabarty Intrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity Molecular Neurodegeneration α-synuclein Amyloid Prion Striatum Dopaminergic Neurodegeneration Astrocyte |
| title | Intrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity |
| title_full | Intrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity |
| title_fullStr | Intrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity |
| title_full_unstemmed | Intrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity |
| title_short | Intrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity |
| title_sort | intrastriatal injection of α synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity |
| topic | α-synuclein Amyloid Prion Striatum Dopaminergic Neurodegeneration Astrocyte |
| url | http://link.springer.com/article/10.1186/s13024-017-0182-z |
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