Post‐inflammatory administration of N‐acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease
Abstract Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease with a prevalence of 1% over the age of 55. Neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies that contain...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-07-01
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| Series: | FASEB BioAdvances |
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| Online Access: | https://doi.org/10.1096/fba.2022-00145 |
| _version_ | 1797787003283046400 |
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| author | Zeynep Bengisu Kaya Elif Karakoc Pamela J. McLean Esen Saka Pergin Atilla |
| author_facet | Zeynep Bengisu Kaya Elif Karakoc Pamela J. McLean Esen Saka Pergin Atilla |
| author_sort | Zeynep Bengisu Kaya |
| collection | DOAJ |
| description | Abstract Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease with a prevalence of 1% over the age of 55. Neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies that contain a variety of proteins and lipids including alpha‐synuclein (α‐syn). Although the formation of α‐syn occurs intracellularly, it can also be found in the extracellular space where it can be taken up by neighboring cells. Toll‐like receptor 2 (TLR2) is an immune system receptor that has been shown to recognize extracellular α‐syn and modulate its uptake by other cells. Lymphocyte‐activation gene 3 (LAG3), an immune checkpoint receptor, has also been proposed to play a role in extracellular α‐syn internalization; however, a recent study has disputed this role. Internalized α‐syn can trigger expression and secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐1β, IL‐2, and IL‐6 and induce neuroinflammation, apoptosis, and mitophagy that results in cellular death. In this study, we tested if N‐acetylcysteine (NAC), an anti‐inflammatory and anti‐carcinogenic drug, can circumvent the detrimental effects of neuroinflammation and induce an anti‐inflammatory response by modulating transcription and expression of TLR2 and LAG3 receptors. Cells overexpressing wild‐type α‐syn were treated with TNF‐α to induce inflammation followed by NAC to inhibit the deleterious effects of TNF‐α‐induced inflammation and apoptosis. SNCA gene transcription and α‐syn protein expression were validated by q‐PCR and Western blot (WB), respectively. Cell viability was measured, and apoptosis was evaluated by WB and terminal deoxynucleotidyl transferase nick end labeling methods. Alterations in LAG3 and TLR2 receptor levels were evaluated by immunofluorescent labeling, WB, and q‐PCR. TNF‐α not only increased inflammation but also increased endogenous and overexpressed α‐syn levels. NAC treatment decreased expression of TLR2 and increased transcription of LAG3 receptor and diminished inflammation‐mediated toxicity and cell death. Here, we demonstrate that NAC can reduce neuroinflammation that occurs as a result of alpha‐synuclein overexpression, via a TLR2‐associated pathway, making it a promising candidate for therapeutic intervention. Further studies are needed to elucidate molecular mechanisms and pathways related to neuroinflammation in PD and to develop possible new therapeutic approaches to slow the clinical progression of PD. |
| first_indexed | 2024-03-13T01:15:49Z |
| format | Article |
| id | doaj.art-a5823538e45146a2a43cf94639a413c7 |
| institution | Directory Open Access Journal |
| issn | 2573-9832 |
| language | English |
| last_indexed | 2024-03-13T01:15:49Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | FASEB BioAdvances |
| spelling | doaj.art-a5823538e45146a2a43cf94639a413c72023-07-05T10:51:44ZengWileyFASEB BioAdvances2573-98322023-07-015726327610.1096/fba.2022-00145Post‐inflammatory administration of N‐acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's diseaseZeynep Bengisu Kaya0Elif Karakoc1Pamela J. McLean2Esen Saka3Pergin Atilla4Department of Neuroscience Mayo Clinic Jacksonville Florida USADepartment of Histology and Embryology Hacettepe University Faculty of Medicine Ankara TurkeyDepartment of Neuroscience Mayo Clinic Jacksonville Florida USADepartment of Neurology Hacettepe University Faculty of Medicine Ankara TurkeyDepartment of Histology and Embryology Hacettepe University Faculty of Medicine Ankara TurkeyAbstract Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease with a prevalence of 1% over the age of 55. Neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies that contain a variety of proteins and lipids including alpha‐synuclein (α‐syn). Although the formation of α‐syn occurs intracellularly, it can also be found in the extracellular space where it can be taken up by neighboring cells. Toll‐like receptor 2 (TLR2) is an immune system receptor that has been shown to recognize extracellular α‐syn and modulate its uptake by other cells. Lymphocyte‐activation gene 3 (LAG3), an immune checkpoint receptor, has also been proposed to play a role in extracellular α‐syn internalization; however, a recent study has disputed this role. Internalized α‐syn can trigger expression and secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐1β, IL‐2, and IL‐6 and induce neuroinflammation, apoptosis, and mitophagy that results in cellular death. In this study, we tested if N‐acetylcysteine (NAC), an anti‐inflammatory and anti‐carcinogenic drug, can circumvent the detrimental effects of neuroinflammation and induce an anti‐inflammatory response by modulating transcription and expression of TLR2 and LAG3 receptors. Cells overexpressing wild‐type α‐syn were treated with TNF‐α to induce inflammation followed by NAC to inhibit the deleterious effects of TNF‐α‐induced inflammation and apoptosis. SNCA gene transcription and α‐syn protein expression were validated by q‐PCR and Western blot (WB), respectively. Cell viability was measured, and apoptosis was evaluated by WB and terminal deoxynucleotidyl transferase nick end labeling methods. Alterations in LAG3 and TLR2 receptor levels were evaluated by immunofluorescent labeling, WB, and q‐PCR. TNF‐α not only increased inflammation but also increased endogenous and overexpressed α‐syn levels. NAC treatment decreased expression of TLR2 and increased transcription of LAG3 receptor and diminished inflammation‐mediated toxicity and cell death. Here, we demonstrate that NAC can reduce neuroinflammation that occurs as a result of alpha‐synuclein overexpression, via a TLR2‐associated pathway, making it a promising candidate for therapeutic intervention. Further studies are needed to elucidate molecular mechanisms and pathways related to neuroinflammation in PD and to develop possible new therapeutic approaches to slow the clinical progression of PD.https://doi.org/10.1096/fba.2022-00145alpha‐synuclein (α‐syn)apoptosisN‐acetylcysteine (NAC)neuroinflammationParkinson's disease |
| spellingShingle | Zeynep Bengisu Kaya Elif Karakoc Pamela J. McLean Esen Saka Pergin Atilla Post‐inflammatory administration of N‐acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease FASEB BioAdvances alpha‐synuclein (α‐syn) apoptosis N‐acetylcysteine (NAC) neuroinflammation Parkinson's disease |
| title | Post‐inflammatory administration of N‐acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease |
| title_full | Post‐inflammatory administration of N‐acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease |
| title_fullStr | Post‐inflammatory administration of N‐acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease |
| title_full_unstemmed | Post‐inflammatory administration of N‐acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease |
| title_short | Post‐inflammatory administration of N‐acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease |
| title_sort | post inflammatory administration of n acetylcysteine reduces inflammation and alters receptor levels in a cellular model of parkinson s disease |
| topic | alpha‐synuclein (α‐syn) apoptosis N‐acetylcysteine (NAC) neuroinflammation Parkinson's disease |
| url | https://doi.org/10.1096/fba.2022-00145 |
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