Altered levels of variant cholinesterase transcripts contribute to the imbalanced cholinergic signaling in Alzheimer's and Parkinson's disease

• Published in: Frontiers in molecular neuroscience Vol. 15; p. 941467
• Main Authors: Gok, Muslum, Madrer, Nimrod, Zorbaz, Tamara, Bennett, Estelle R, Greenberg, David, Bennett, David A, Soreq, Hermona
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 02.09.2022; Frontiers Media S.A
• Subjects: 3' Untranslated regions; 5' Untranslated Regions; Acetylcholinesterase; Alternative splicing; Alzheimer's disease; Amygdala; Brain; butyrylcholinesterase; Cell culture; Cell differentiation; Cholinesterase; Cognitive ability; Enzymes; Gene regulation; MicroRNAs; Molecular Neuroscience; Movement disorders; Mutation; Neuroblastoma; Neuroblastoma cells; Neurodegeneration; Neurodegenerative diseases; Oxidative stress; Paraquat; Parkinson's disease; Post-transcription; Simvastatin; Single-nucleotide polymorphism; SNPs (single-nucleotide polymorphisms); splice variants; Substantia nigra; Superior temporal gyrus; Temporal gyrus; United States > US; splice variants; acetylcholinesterase; butyrylcholinesterase; Alzheimer’s disease; Parkinson’s disease; SNPs (single-nucleotide polymorphisms)
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2022.941467

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 ( = 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 ( = 79, = 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 ( < 0.05) in the AD superior temporal gyrus and the PD amygdala, but not in the neuron-deprived substantia nigra. Elevated levels of BChE ( < 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).