Cargando…

27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons

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 met...

Descripción completa

Detalles Bibliográficos
Autores principales: Schommer, Jared, Marwarha, Gurdeep, Schommer, Trevor, Flick, Travis, Lund, Jonah, Ghribi, Othman
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883307/
https://www.ncbi.nlm.nih.gov/pubmed/29614969
http://dx.doi.org/10.1186/s12868-018-0420-5
_version_ 1783311622582829056
author Schommer, Jared
Marwarha, Gurdeep
Schommer, Trevor
Flick, Travis
Lund, Jonah
Ghribi, Othman
author_facet Schommer, Jared
Marwarha, Gurdeep
Schommer, Trevor
Flick, Travis
Lund, Jonah
Ghribi, Othman
author_sort Schommer, Jared
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5883307
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-58833072018-04-10 27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons Schommer, Jared Marwarha, Gurdeep Schommer, Trevor Flick, Travis Lund, Jonah Ghribi, Othman BMC Neurosci Research Article 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. BioMed Central 2018-04-03 /pmc/articles/PMC5883307/ /pubmed/29614969 http://dx.doi.org/10.1186/s12868-018-0420-5 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Schommer, Jared
Marwarha, Gurdeep
Schommer, Trevor
Flick, Travis
Lund, Jonah
Ghribi, Othman
27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons
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 Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883307/
https://www.ncbi.nlm.nih.gov/pubmed/29614969
http://dx.doi.org/10.1186/s12868-018-0420-5
work_keys_str_mv AT schommerjared 27hydroxycholesterolincreasesasynucleinproteinlevelsthroughproteasomalinhibitioninhumandopaminergicneurons
AT marwarhagurdeep 27hydroxycholesterolincreasesasynucleinproteinlevelsthroughproteasomalinhibitioninhumandopaminergicneurons
AT schommertrevor 27hydroxycholesterolincreasesasynucleinproteinlevelsthroughproteasomalinhibitioninhumandopaminergicneurons
AT flicktravis 27hydroxycholesterolincreasesasynucleinproteinlevelsthroughproteasomalinhibitioninhumandopaminergicneurons
AT lundjonah 27hydroxycholesterolincreasesasynucleinproteinlevelsthroughproteasomalinhibitioninhumandopaminergicneurons
AT ghribiothman 27hydroxycholesterolincreasesasynucleinproteinlevelsthroughproteasomalinhibitioninhumandopaminergicneurons