Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies.
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. The histopathological hallmark of MSA is glial cytoplasmic inclusions (GCI) within oligodendrocytes, accompanied by neuronal degeneration. MSA is a...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3471961?pdf=render |
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| author | Haya Kisos Katharina Pukaß Tamir Ben-Hur Christiane Richter-Landsberg Ronit Sharon |
| author_facet | Haya Kisos Katharina Pukaß Tamir Ben-Hur Christiane Richter-Landsberg Ronit Sharon |
| author_sort | Haya Kisos |
| collection | DOAJ |
| description | Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. The histopathological hallmark of MSA is glial cytoplasmic inclusions (GCI) within oligodendrocytes, accompanied by neuronal degeneration. MSA is a synucleinopathy, and α-Synuclein (α-Syn) is the major protein constituent of the GCI. It is unclear how the neuronal α-Syn protein accumulates in oligodendrocytes. We tested the hypothesis that oligodendrocytes can take up neuronal-secreted α-Syn as part of the pathogenic mechanisms leading to MSA. We report that increases in the degree of α-Syn soluble oligomers or intracellular α-Syn levels, enhance its secretion from cultured MN9D dopaminergic cells, stably expressing the protein. In accord, we show that primary oligodendrocytes from rat brain and oligodendroglial cell lines take-up neuronal-secreted or exogenously added α-Syn from their conditioning medium. This uptake is concentration-, time-, and clathrin-dependent. Utilizing the demonstrated effect of polyunsaturated fatty acids (PUFA) to enhance α-Syn neuropathology, we show an in vivo effect for brain docosahexaenoic acid (DHA) levels on α-Syn localization to oligodendrocytes in brains of a mouse model for synucleinopathies, expressing human A53T α-Syn cDNA under the PrP promoter. Hence, pathogenic mechanisms leading to elevated levels of α-Syn in neurons underlie neuronal secretion and subsequent uptake of α-Syn by oligodendrocytes in MSA. |
| first_indexed | 2024-04-12T08:05:42Z |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T08:05:42Z |
| publishDate | 2012-01-01 |
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| series | PLoS ONE |
| spelling | doaj.art-6600a5da017f4253af0ff8c2a06424e92022-12-22T03:41:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01710e4681710.1371/journal.pone.0046817Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies.Haya KisosKatharina PukaßTamir Ben-HurChristiane Richter-LandsbergRonit SharonMultiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. The histopathological hallmark of MSA is glial cytoplasmic inclusions (GCI) within oligodendrocytes, accompanied by neuronal degeneration. MSA is a synucleinopathy, and α-Synuclein (α-Syn) is the major protein constituent of the GCI. It is unclear how the neuronal α-Syn protein accumulates in oligodendrocytes. We tested the hypothesis that oligodendrocytes can take up neuronal-secreted α-Syn as part of the pathogenic mechanisms leading to MSA. We report that increases in the degree of α-Syn soluble oligomers or intracellular α-Syn levels, enhance its secretion from cultured MN9D dopaminergic cells, stably expressing the protein. In accord, we show that primary oligodendrocytes from rat brain and oligodendroglial cell lines take-up neuronal-secreted or exogenously added α-Syn from their conditioning medium. This uptake is concentration-, time-, and clathrin-dependent. Utilizing the demonstrated effect of polyunsaturated fatty acids (PUFA) to enhance α-Syn neuropathology, we show an in vivo effect for brain docosahexaenoic acid (DHA) levels on α-Syn localization to oligodendrocytes in brains of a mouse model for synucleinopathies, expressing human A53T α-Syn cDNA under the PrP promoter. Hence, pathogenic mechanisms leading to elevated levels of α-Syn in neurons underlie neuronal secretion and subsequent uptake of α-Syn by oligodendrocytes in MSA.http://europepmc.org/articles/PMC3471961?pdf=render |
| spellingShingle | Haya Kisos Katharina Pukaß Tamir Ben-Hur Christiane Richter-Landsberg Ronit Sharon Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies. PLoS ONE |
| title | Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies. |
| title_full | Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies. |
| title_fullStr | Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies. |
| title_full_unstemmed | Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies. |
| title_short | Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies. |
| title_sort | increased neuronal α synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α synucleinopathies |
| url | http://europepmc.org/articles/PMC3471961?pdf=render |
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