Altered levels of variant cholinesterase transcripts contribute to the imbalanced cholinergic signaling in Alzheimer’s and Parkinson’s disease
Acetylcholinesterase and butyrylcholinesterase (AChE and BChE) are involved in modulating cholinergic signaling, but their roles in Alzheimer’s and Parkinson’s diseases (AD and PD) remain unclear. We identified a higher frequency of the functionally impaired BCHE-K variant (rs1803274) in AD and PD c...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.941467/full |
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| author | Muslum Gok Muslum Gok Nimrod Madrer Nimrod Madrer Tamara Zorbaz Tamara Zorbaz Estelle R. Bennett Estelle R. Bennett David Greenberg David Greenberg David A. Bennett Hermona Soreq Hermona Soreq |
| author_facet | Muslum Gok Muslum Gok Nimrod Madrer Nimrod Madrer Tamara Zorbaz Tamara Zorbaz Estelle R. Bennett Estelle R. Bennett David Greenberg David Greenberg David A. Bennett Hermona Soreq Hermona Soreq |
| author_sort | Muslum Gok |
| collection | DOAJ |
| description | Acetylcholinesterase and butyrylcholinesterase (AChE and BChE) are involved in modulating cholinergic signaling, but their roles in Alzheimer’s and Parkinson’s diseases (AD and PD) remain unclear. We identified a higher frequency of the functionally impaired BCHE-K variant (rs1803274) in AD and PD compared to controls and lower than in the GTEx dataset of healthy individuals (n = 651); in comparison, the prevalence of the 5′-UTR (rs1126680) and intron 2 (rs55781031) single-nucleotide polymorphisms (SNPs) of BCHE and ACHE’s 3′-UTR (rs17228616) which disrupt AChE mRNA targeting by miR-608 remained unchanged. qPCR validations confirmed lower levels of the dominant splice variant encoding the “synaptic” membrane-bound ACHE-S in human post-mortem superior temporal gyrus samples from AD and in substantia nigra (but not amygdala) samples from PD patients (n = 79, n = 67) compared to controls, potentially reflecting region-specific loss of cholinergic neurons. In contradistinction, the non-dominant “readthrough” AChE-R mRNA variant encoding for soluble AChE was elevated (p < 0.05) in the AD superior temporal gyrus and the PD amygdala, but not in the neuron-deprived substantia nigra. Elevated levels of BChE (p < 0.001) were seen in AD superior temporal gyrus. Finally, all three ACHE splice variants, AChE-S, AChE-R, and N-extended AChE, were elevated in cholinergic-differentiated human neuroblastoma cells, with exposure to the oxidative stress agent paraquat strongly downregulating AChE-S and BChE, inverse to their upregulation under exposure to the antioxidant simvastatin. The multi-leveled changes in cholinesterase balance highlight the role of post-transcriptional regulation in neurodegeneration. (235) |
| first_indexed | 2024-04-11T13:27:07Z |
| format | Article |
| id | doaj.art-c2b9d62a14fa477fa1232ffcfb5df553 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-11T13:27:07Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-c2b9d62a14fa477fa1232ffcfb5df5532022-12-22T04:22:01ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-09-011510.3389/fnmol.2022.941467941467Altered levels of variant cholinesterase transcripts contribute to the imbalanced cholinergic signaling in Alzheimer’s and Parkinson’s diseaseMuslum Gok0Muslum Gok1Nimrod Madrer2Nimrod Madrer3Tamara Zorbaz4Tamara Zorbaz5Estelle R. Bennett6Estelle R. Bennett7David Greenberg8David Greenberg9David A. Bennett10Hermona Soreq11Hermona Soreq12Department of Biochemistry, Faculty of Medicine, Muğla Sıtkı Koçman University, Muğla, TurkeyEdmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, IsraelEdmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, IsraelEdmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, IsraelBiochemistry and Organic Analytical Chemistry Unit, Institute for Medical Research and Occupational Health, Zagreb, CroatiaEdmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, IsraelEdmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL, United StatesEdmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, IsraelAcetylcholinesterase and butyrylcholinesterase (AChE and BChE) are involved in modulating cholinergic signaling, but their roles in Alzheimer’s and Parkinson’s diseases (AD and PD) remain unclear. We identified a higher frequency of the functionally impaired BCHE-K variant (rs1803274) in AD and PD compared to controls and lower than in the GTEx dataset of healthy individuals (n = 651); in comparison, the prevalence of the 5′-UTR (rs1126680) and intron 2 (rs55781031) single-nucleotide polymorphisms (SNPs) of BCHE and ACHE’s 3′-UTR (rs17228616) which disrupt AChE mRNA targeting by miR-608 remained unchanged. qPCR validations confirmed lower levels of the dominant splice variant encoding the “synaptic” membrane-bound ACHE-S in human post-mortem superior temporal gyrus samples from AD and in substantia nigra (but not amygdala) samples from PD patients (n = 79, n = 67) compared to controls, potentially reflecting region-specific loss of cholinergic neurons. In contradistinction, the non-dominant “readthrough” AChE-R mRNA variant encoding for soluble AChE was elevated (p < 0.05) in the AD superior temporal gyrus and the PD amygdala, but not in the neuron-deprived substantia nigra. Elevated levels of BChE (p < 0.001) were seen in AD superior temporal gyrus. Finally, all three ACHE splice variants, AChE-S, AChE-R, and N-extended AChE, were elevated in cholinergic-differentiated human neuroblastoma cells, with exposure to the oxidative stress agent paraquat strongly downregulating AChE-S and BChE, inverse to their upregulation under exposure to the antioxidant simvastatin. The multi-leveled changes in cholinesterase balance highlight the role of post-transcriptional regulation in neurodegeneration. (235)https://www.frontiersin.org/articles/10.3389/fnmol.2022.941467/fullAlzheimer’s diseaseParkinson’s diseaseacetylcholinesterasebutyrylcholinesteraseSNPs (single-nucleotide polymorphisms)splice variants |
| spellingShingle | Muslum Gok Muslum Gok Nimrod Madrer Nimrod Madrer Tamara Zorbaz Tamara Zorbaz Estelle R. Bennett Estelle R. Bennett David Greenberg David Greenberg David A. Bennett Hermona Soreq Hermona Soreq Altered levels of variant cholinesterase transcripts contribute to the imbalanced cholinergic signaling in Alzheimer’s and Parkinson’s disease Frontiers in Molecular Neuroscience Alzheimer’s disease Parkinson’s disease acetylcholinesterase butyrylcholinesterase SNPs (single-nucleotide polymorphisms) splice variants |
| title | Altered levels of variant cholinesterase transcripts contribute to the imbalanced cholinergic signaling in Alzheimer’s and Parkinson’s disease |
| title_full | Altered levels of variant cholinesterase transcripts contribute to the imbalanced cholinergic signaling in Alzheimer’s and Parkinson’s disease |
| title_fullStr | Altered levels of variant cholinesterase transcripts contribute to the imbalanced cholinergic signaling in Alzheimer’s and Parkinson’s disease |
| title_full_unstemmed | Altered levels of variant cholinesterase transcripts contribute to the imbalanced cholinergic signaling in Alzheimer’s and Parkinson’s disease |
| title_short | Altered levels of variant cholinesterase transcripts contribute to the imbalanced cholinergic signaling in Alzheimer’s and Parkinson’s disease |
| title_sort | altered levels of variant cholinesterase transcripts contribute to the imbalanced cholinergic signaling in alzheimer s and parkinson s disease |
| topic | Alzheimer’s disease Parkinson’s disease acetylcholinesterase butyrylcholinesterase SNPs (single-nucleotide polymorphisms) splice variants |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.941467/full |
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