Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration
Abstract Misfolded alpha-synuclein (αSyn) is a major constituent of Lewy bodies and Lewy neurites, which are pathological hallmarks of Parkinson’s disease (PD). The contribution of αSyn to PD is well established, but the detailed mechanism remains obscure. Using a model in which αSyn aggregation in...
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doaj-fb0bbddddb9e4da18dd59b561c49ab952020-11-25T02:28:12ZengBMCActa Neuropathologica Communications2051-59602019-03-017111410.1186/s40478-019-0696-4Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respirationXinhe Wang0Katelyn Becker1Nathan Levine2Michelle Zhang3Andrew P. Lieberman4Darren J. Moore5Jiyan Ma6Center for Neurodegenerative Science, Van Andel Research InstituteCenter for Neurodegenerative Science, Van Andel Research InstituteCenter for Neurodegenerative Science, Van Andel Research InstituteCenter for Neurodegenerative Science, Van Andel Research InstituteDepartment of Pathology, University of Michigan Medical SchoolCenter for Neurodegenerative Science, Van Andel Research InstituteCenter for Neurodegenerative Science, Van Andel Research InstituteAbstract Misfolded alpha-synuclein (αSyn) is a major constituent of Lewy bodies and Lewy neurites, which are pathological hallmarks of Parkinson’s disease (PD). The contribution of αSyn to PD is well established, but the detailed mechanism remains obscure. Using a model in which αSyn aggregation in primary neurons was seeded by exogenously added, preformed αSyn amyloid fibrils (PFF), we found that a majority of pathogenic αSyn (indicated by serine 129 phosphorylated αSyn, ps-αSyn) was membrane-bound and associated with mitochondria. In contrast, only a minuscule amount of physiological αSyn was mitochondrial bound. In vitro, αSyn PFF displayed a stronger binding to purified mitochondria than did αSyn monomer, revealing a preferential mitochondria binding by aggregated αSyn. This selective mitochondrial ps-αSyn accumulation was confirmed in other neuronal and animal αSyn aggregation models that do not require exogenously added PFF and, more importantly, in postmortem brain tissues of patients suffering from PD and other neurodegenerative diseases with αSyn aggregation (α-synucleinopathies). We also showed that the mitochondrial ps-αSyn accumulation was accompanied by defects in cellular respiration in primary neurons, suggesting a link to mitochondrial dysfunction. Together, our results show that, contrary to physiological αSyn, pathogenic αSyn aggregates preferentially bind to mitochondria, indicating mitochondrial dysfunction as the common downstream mechanism for α-synucleinopathies. Our findings suggest a plausible model explaining the formation and the peculiar morphology of Lewy body and reveal that disrupting the interaction between ps-αSyn and the mitochondria is a therapeutic target for α-synucleinopathies.http://link.springer.com/article/10.1186/s40478-019-0696-4α-SynucleinAggregationPFFMitochondriaLewy bodyParkinson’s disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xinhe Wang Katelyn Becker Nathan Levine Michelle Zhang Andrew P. Lieberman Darren J. Moore Jiyan Ma |
spellingShingle |
Xinhe Wang Katelyn Becker Nathan Levine Michelle Zhang Andrew P. Lieberman Darren J. Moore Jiyan Ma Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration Acta Neuropathologica Communications α-Synuclein Aggregation PFF Mitochondria Lewy body Parkinson’s disease |
author_facet |
Xinhe Wang Katelyn Becker Nathan Levine Michelle Zhang Andrew P. Lieberman Darren J. Moore Jiyan Ma |
author_sort |
Xinhe Wang |
title |
Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration |
title_short |
Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration |
title_full |
Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration |
title_fullStr |
Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration |
title_full_unstemmed |
Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration |
title_sort |
pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2019-03-01 |
description |
Abstract Misfolded alpha-synuclein (αSyn) is a major constituent of Lewy bodies and Lewy neurites, which are pathological hallmarks of Parkinson’s disease (PD). The contribution of αSyn to PD is well established, but the detailed mechanism remains obscure. Using a model in which αSyn aggregation in primary neurons was seeded by exogenously added, preformed αSyn amyloid fibrils (PFF), we found that a majority of pathogenic αSyn (indicated by serine 129 phosphorylated αSyn, ps-αSyn) was membrane-bound and associated with mitochondria. In contrast, only a minuscule amount of physiological αSyn was mitochondrial bound. In vitro, αSyn PFF displayed a stronger binding to purified mitochondria than did αSyn monomer, revealing a preferential mitochondria binding by aggregated αSyn. This selective mitochondrial ps-αSyn accumulation was confirmed in other neuronal and animal αSyn aggregation models that do not require exogenously added PFF and, more importantly, in postmortem brain tissues of patients suffering from PD and other neurodegenerative diseases with αSyn aggregation (α-synucleinopathies). We also showed that the mitochondrial ps-αSyn accumulation was accompanied by defects in cellular respiration in primary neurons, suggesting a link to mitochondrial dysfunction. Together, our results show that, contrary to physiological αSyn, pathogenic αSyn aggregates preferentially bind to mitochondria, indicating mitochondrial dysfunction as the common downstream mechanism for α-synucleinopathies. Our findings suggest a plausible model explaining the formation and the peculiar morphology of Lewy body and reveal that disrupting the interaction between ps-αSyn and the mitochondria is a therapeutic target for α-synucleinopathies. |
topic |
α-Synuclein Aggregation PFF Mitochondria Lewy body Parkinson’s disease |
url |
http://link.springer.com/article/10.1186/s40478-019-0696-4 |
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