Differential, Stage Dependent Detection of Peptidylarginine Deiminases and Protein Deimination in Lewy Body Diseases—Findings from a Pilot Study
Over 10 million people worldwide live with Parkinson’s disease (PD) and 4% of affected people are diagnosed before the age of 50. Research on early PD-related pathways is therefore of considerable importance. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that, through...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/21/13117 |
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| author | Audrey Mercer Zane Jaunmuktane Mariya Hristova Sigrun Lange |
| author_facet | Audrey Mercer Zane Jaunmuktane Mariya Hristova Sigrun Lange |
| author_sort | Audrey Mercer |
| collection | DOAJ |
| description | Over 10 million people worldwide live with Parkinson’s disease (PD) and 4% of affected people are diagnosed before the age of 50. Research on early PD-related pathways is therefore of considerable importance. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that, through post-translational deimination of arginine to citrulline, contribute to changes in protein function, including in pathological processes. Recent studies have highlighted roles for PADs in a range of neurological disorders including PD, but overall, investigations on PADs in Lewy body disease (LBD), including PD, are still scarce. Hence, the current pilot study aimed at performing an immunohistochemistry screen of post-mortem human brain sections from Braak stages 4-6 from PD patients, as well as patients with incidental LBD (ILBD). We assessed differences in PAD isozyme detection (assessing all five PADs), in total protein deimination/citrullination and histone H3 deimination—which is an indicator of epigenetic changes and extracellular trap formation (ETosis), which can elicit immune responses and has involvement in pathogenic conditions. The findings of our pilot study indicate that PADs and deimination are increased in cingulate cortex and hippocampus, particularly in earlier stages of the disease. PAD2 and PAD3 were the most strongly upregulated PAD isozymes, with some elevation also observed for PAD1, while PAD4 and PAD6 increase was less marked in PD brains. Total protein deimination and histone H3 deimination were furthermore increased in PD brains, with a considerable increase at earlier Braak stages, compared with controls. Our findings point to a significant contribution of PADs, which may further aid early disease biomarker discovery, in PD and other LBDs. |
| first_indexed | 2024-03-09T19:00:24Z |
| format | Article |
| id | doaj.art-3219f8d9cf284360a1efdbc9184cfb46 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:00:24Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3219f8d9cf284360a1efdbc9184cfb462023-11-24T05:02:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123211311710.3390/ijms232113117Differential, Stage Dependent Detection of Peptidylarginine Deiminases and Protein Deimination in Lewy Body Diseases—Findings from a Pilot StudyAudrey Mercer0Zane Jaunmuktane1Mariya Hristova2Sigrun Lange3Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UKDepartment of Clinical and Movement Neurosciences, Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UKPerinatal Brain Repair Group, Department of Neonatology, UCL Institute for Women’s Health, London WC1E 6HU, UKTissue Architecture and Regeneration Research Group, School of Life Sciences, University of Westminster, London W1W 6XH, UKOver 10 million people worldwide live with Parkinson’s disease (PD) and 4% of affected people are diagnosed before the age of 50. Research on early PD-related pathways is therefore of considerable importance. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that, through post-translational deimination of arginine to citrulline, contribute to changes in protein function, including in pathological processes. Recent studies have highlighted roles for PADs in a range of neurological disorders including PD, but overall, investigations on PADs in Lewy body disease (LBD), including PD, are still scarce. Hence, the current pilot study aimed at performing an immunohistochemistry screen of post-mortem human brain sections from Braak stages 4-6 from PD patients, as well as patients with incidental LBD (ILBD). We assessed differences in PAD isozyme detection (assessing all five PADs), in total protein deimination/citrullination and histone H3 deimination—which is an indicator of epigenetic changes and extracellular trap formation (ETosis), which can elicit immune responses and has involvement in pathogenic conditions. The findings of our pilot study indicate that PADs and deimination are increased in cingulate cortex and hippocampus, particularly in earlier stages of the disease. PAD2 and PAD3 were the most strongly upregulated PAD isozymes, with some elevation also observed for PAD1, while PAD4 and PAD6 increase was less marked in PD brains. Total protein deimination and histone H3 deimination were furthermore increased in PD brains, with a considerable increase at earlier Braak stages, compared with controls. Our findings point to a significant contribution of PADs, which may further aid early disease biomarker discovery, in PD and other LBDs.https://www.mdpi.com/1422-0067/23/21/13117peptidylarginine deiminasedeimination/citrullinationpost-translational modificationhistone H3neurodegenerationParkinson’s disease |
| spellingShingle | Audrey Mercer Zane Jaunmuktane Mariya Hristova Sigrun Lange Differential, Stage Dependent Detection of Peptidylarginine Deiminases and Protein Deimination in Lewy Body Diseases—Findings from a Pilot Study International Journal of Molecular Sciences peptidylarginine deiminase deimination/citrullination post-translational modification histone H3 neurodegeneration Parkinson’s disease |
| title | Differential, Stage Dependent Detection of Peptidylarginine Deiminases and Protein Deimination in Lewy Body Diseases—Findings from a Pilot Study |
| title_full | Differential, Stage Dependent Detection of Peptidylarginine Deiminases and Protein Deimination in Lewy Body Diseases—Findings from a Pilot Study |
| title_fullStr | Differential, Stage Dependent Detection of Peptidylarginine Deiminases and Protein Deimination in Lewy Body Diseases—Findings from a Pilot Study |
| title_full_unstemmed | Differential, Stage Dependent Detection of Peptidylarginine Deiminases and Protein Deimination in Lewy Body Diseases—Findings from a Pilot Study |
| title_short | Differential, Stage Dependent Detection of Peptidylarginine Deiminases and Protein Deimination in Lewy Body Diseases—Findings from a Pilot Study |
| title_sort | differential stage dependent detection of peptidylarginine deiminases and protein deimination in lewy body diseases findings from a pilot study |
| topic | peptidylarginine deiminase deimination/citrullination post-translational modification histone H3 neurodegeneration Parkinson’s disease |
| url | https://www.mdpi.com/1422-0067/23/21/13117 |
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