AUTHOR=Gok Muslum , Madrer Nimrod , Zorbaz Tamara , Bennett Estelle R. , Greenberg David , Bennett David A. , Soreq Hermona 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 15 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.941467

DOI=10.3389/fnmol.2022.941467

ISSN=1662-5099

ABSTRACT=Acetylcholinesterase and butyrylcholinesterase (AChE, BChE) are involved in modulating cholinergic signaling, but their roles in Alzheimer's and Parkinson's diseases (AD, PD) remain unclear. We identified a higher frequency of the functionally impaired BCHE-K variant (rs1803274) in AD and PD compared to controls (p < 0.05) and to 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.