27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons
Abstract Background Accumulation of the α-synuclein (α-syn) protein is a hallmark of a group of brain disorders collectively known as synucleinopathies. The mechanisms responsible for α-syn accumulation are not well understood. Several studies suggest a link between synucleinopathies and the cholest...
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BMC
2018-04-01
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| Series: | BMC Neuroscience |
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| Online Access: | http://link.springer.com/article/10.1186/s12868-018-0420-5 |
| _version_ | 1818792292626989056 |
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| author | Jared Schommer Gurdeep Marwarha Trevor Schommer Travis Flick Jonah Lund Othman Ghribi |
| author_facet | Jared Schommer Gurdeep Marwarha Trevor Schommer Travis Flick Jonah Lund Othman Ghribi |
| author_sort | Jared Schommer |
| collection | DOAJ |
| description | Abstract Background Accumulation of the α-synuclein (α-syn) protein is a hallmark of a group of brain disorders collectively known as synucleinopathies. The mechanisms responsible for α-syn accumulation are not well understood. Several studies suggest a link between synucleinopathies and the cholesterol metabolite 27-hydroxycholesterol (27-OHC). 27-OHC is the major cholesterol metabolite in the blood that crosses the blood brain barrier, and its levels can increase following hypercholesterolemia, aging, and oxidative stress, which are all factors for increased synucleinopathy risk. In this study, we determined the extent to which 27-OHC regulates α-syn levels in human dopaminergic neurons, the cell type in which α-syn accumulates in PD, a major synucleinopathy disorder. Results Our results show that 27-OHC significantly increases the protein levels, not the mRNA expression of α-syn. The effects of 27-OHC appear to be independent of an action through liver X receptors (LXR), its cognate receptors, as the LXR agonist, GW3965, or the LXR antagonist ECHS did not affect α-syn protein or mRNA levels. Furthermore, our data strongly suggest that the 27-OHC-induced increase in α-syn protein levels emanates from inhibition of the proteasomal degradation of this protein and a decrease in the heat shock protein 70 (HSP70). Conclusions Identifying 27-OHC as a factor that can increase α-syn levels and the inhibition of the proteasomal function and reduction in HSP70 levels as potential cellular mechanisms involved in regulation of α-syn. This may help in targeting the correct degradation of α-syn as a potential avenue to preclude α-syn accumulation. |
| first_indexed | 2024-12-18T15:24:56Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1471-2202 |
| language | English |
| last_indexed | 2024-12-18T15:24:56Z |
| publishDate | 2018-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Neuroscience |
| spelling | doaj.art-f60f57a0a347479491425c80dbcdba182022-12-21T21:03:17ZengBMCBMC Neuroscience1471-22022018-04-0119111210.1186/s12868-018-0420-527-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neuronsJared Schommer0Gurdeep Marwarha1Trevor Schommer2Travis Flick3Jonah Lund4Othman Ghribi5Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North DakotaDepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of North DakotaDepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of North DakotaDepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of North DakotaDepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of North DakotaDepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of North DakotaAbstract Background Accumulation of the α-synuclein (α-syn) protein is a hallmark of a group of brain disorders collectively known as synucleinopathies. The mechanisms responsible for α-syn accumulation are not well understood. Several studies suggest a link between synucleinopathies and the cholesterol metabolite 27-hydroxycholesterol (27-OHC). 27-OHC is the major cholesterol metabolite in the blood that crosses the blood brain barrier, and its levels can increase following hypercholesterolemia, aging, and oxidative stress, which are all factors for increased synucleinopathy risk. In this study, we determined the extent to which 27-OHC regulates α-syn levels in human dopaminergic neurons, the cell type in which α-syn accumulates in PD, a major synucleinopathy disorder. Results Our results show that 27-OHC significantly increases the protein levels, not the mRNA expression of α-syn. The effects of 27-OHC appear to be independent of an action through liver X receptors (LXR), its cognate receptors, as the LXR agonist, GW3965, or the LXR antagonist ECHS did not affect α-syn protein or mRNA levels. Furthermore, our data strongly suggest that the 27-OHC-induced increase in α-syn protein levels emanates from inhibition of the proteasomal degradation of this protein and a decrease in the heat shock protein 70 (HSP70). Conclusions Identifying 27-OHC as a factor that can increase α-syn levels and the inhibition of the proteasomal function and reduction in HSP70 levels as potential cellular mechanisms involved in regulation of α-syn. This may help in targeting the correct degradation of α-syn as a potential avenue to preclude α-syn accumulation.http://link.springer.com/article/10.1186/s12868-018-0420-527-HydroxycholesterolΑlpha-synucleinLiver X receptorParkinson’s diseaseDopaminergic neuronsProteasomal dysfunction |
| spellingShingle | Jared Schommer Gurdeep Marwarha Trevor Schommer Travis Flick Jonah Lund Othman Ghribi 27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons BMC Neuroscience 27-Hydroxycholesterol Αlpha-synuclein Liver X receptor Parkinson’s disease Dopaminergic neurons Proteasomal dysfunction |
| title | 27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons |
| title_full | 27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons |
| title_fullStr | 27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons |
| title_full_unstemmed | 27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons |
| title_short | 27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons |
| title_sort | 27 hydroxycholesterol increases α synuclein protein levels through proteasomal inhibition in human dopaminergic neurons |
| topic | 27-Hydroxycholesterol Αlpha-synuclein Liver X receptor Parkinson’s disease Dopaminergic neurons Proteasomal dysfunction |
| url | http://link.springer.com/article/10.1186/s12868-018-0420-5 |
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