Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease
Abstract Alpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson’s disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and oth...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-03-01
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| Series: | Acta Neuropathologica Communications |
| Online Access: | https://doi.org/10.1186/s40478-021-01136-3 |
| _version_ | 1818610039035789312 |
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| author | Juan F. Reyes Sara Ekmark-Léwen Marina Perdiki Therése Klingstedt Alana Hoffmann Emilia Wiechec Per Nilsson K. Peter R. Nilsson Irina Alafuzoff Martin Ingelsson Martin Hallbeck |
| author_facet | Juan F. Reyes Sara Ekmark-Léwen Marina Perdiki Therése Klingstedt Alana Hoffmann Emilia Wiechec Per Nilsson K. Peter R. Nilsson Irina Alafuzoff Martin Ingelsson Martin Hallbeck |
| author_sort | Juan F. Reyes |
| collection | DOAJ |
| description | Abstract Alpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson’s disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric α-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of α-syn within the liver of three different transgenic (tg) mouse models expressing human α-syn under CNS-specific promoters, despite the lack of α-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of α-syn pathology within the liver of wild type mice one month after a single striatal α-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Aß) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed α-syn pathology containing α-syn within hepatocellular structures to a higher degree (75%) than control subjects without α-syn accumulation in the brain (57%). Our results reveal that α-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies. |
| first_indexed | 2024-12-16T15:08:05Z |
| format | Article |
| id | doaj.art-d3b37dfdd451474997f2e1e5c9a5e227 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-16T15:08:05Z |
| publishDate | 2021-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-d3b37dfdd451474997f2e1e5c9a5e2272022-12-21T22:27:04ZengBMCActa Neuropathologica Communications2051-59602021-03-019112010.1186/s40478-021-01136-3Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s diseaseJuan F. Reyes0Sara Ekmark-Léwen1Marina Perdiki2Therése Klingstedt3Alana Hoffmann4Emilia Wiechec5Per Nilsson6K. Peter R. Nilsson7Irina Alafuzoff8Martin Ingelsson9Martin Hallbeck10Department of Biomedical and Clinical Sciences (BKV), Linköping UniversityDepartment of Public Health and Caring Sciences, Section of Geriatrics, Uppsala UniversityDepartment of Biomedical and Clinical Sciences (BKV), Linköping UniversityDepartment of Physics, Chemistry and Biology, Linköping UniversityDepartment of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergDepartment of Biomedical and Clinical Sciences (BKV), Linköping UniversityDepartment of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska InstitutetDepartment of Physics, Chemistry and Biology, Linköping UniversityDepartment of Pathology, Uppsala University HospitalDepartment of Public Health and Caring Sciences, Section of Geriatrics, Uppsala UniversityDepartment of Biomedical and Clinical Sciences (BKV), Linköping UniversityAbstract Alpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson’s disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric α-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of α-syn within the liver of three different transgenic (tg) mouse models expressing human α-syn under CNS-specific promoters, despite the lack of α-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of α-syn pathology within the liver of wild type mice one month after a single striatal α-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Aß) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed α-syn pathology containing α-syn within hepatocellular structures to a higher degree (75%) than control subjects without α-syn accumulation in the brain (57%). Our results reveal that α-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.https://doi.org/10.1186/s40478-021-01136-3 |
| spellingShingle | Juan F. Reyes Sara Ekmark-Léwen Marina Perdiki Therése Klingstedt Alana Hoffmann Emilia Wiechec Per Nilsson K. Peter R. Nilsson Irina Alafuzoff Martin Ingelsson Martin Hallbeck Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease Acta Neuropathologica Communications |
| title | Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease |
| title_full | Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease |
| title_fullStr | Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease |
| title_full_unstemmed | Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease |
| title_short | Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease |
| title_sort | accumulation of alpha synuclein within the liver potential role in the clearance of brain pathology associated with parkinson s disease |
| url | https://doi.org/10.1186/s40478-021-01136-3 |
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