Alexander Silberman Institute of Life Sciences, Hebrew University, Israel

Hermona Soreq is the Charlotte Slesinger Professor of Molecular Biology at the Hebrew University’s Alexander Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Sciences. A leader in the field of cholinesterase activities and their functions in the brain and periphery, Soreq won honorary PhD degrees from Stockholm (1996), Erlangen-Nuremberg (2007) and Beer-Sheva (2007) as well as an Israeli Ministry of Health Prize (2000), Landau Prize for Biomedical Research (2005), Teva Prize for Molecular Medicine (2006), The Rappaport Prize for Biomedical research (2014), the Katzir Prize for Life Sciences, 2017), the Lise Meitner Alexander Humboldt Research Prize, 2009, an advanced ERC award and two proof-of-concept ERC awards, 2013-2018 and a Neuroinflammation award, 2016. A council member of the International Society of Neurochemistry (2017-2019), Soreq is the president of the International organization for cholinergic mechanisms (2010-). She is the author of over 275 publications, including 54 published in Science, Nature, PNAS and other high-impact journals, with H-index of 82.

Speech Title: Exploring non-coding RNA regulators of acetylcholine functioning

Abstract: The parasympathetic system coordinates multiple body functions by maintaining efficient and rapidly adgustable surveillance over acetylcholine (ACh) hydrolysis rates, but the molecular regulators of its brain-to-body messages are incompletely understood. Our studies are focused on the regulation of ACh functioning by non-coding RNAs, especially MicroRNAs (miRs), which have rapidly emerged as global controllers of gene expression. We investigate ACh-related miR functions in the healthy and diseased brain by combining advanced RNA-sequencing technologies with computational neuroscience and transgenic engineering tools and with the in vivo administration of synthetic oligonucleotide suppressors of our miR candidates. Using these approaches, we discovered "CholinomiR" silencers of multiple cholinergic brain-to-body communication-related genes, which compete with each other on suppressing anxiety, epilepsy, mental disease and metabolic targets. To test CholinomiR-based intervention with diseases involving impaired ACh signalling, we engineered mice over-expressing the soluble stress-induced acetylcholinesterase splice variant AChE-R but depleted the miR-reacting domain from this transgene. This mouse model demonstrated elevated CholinomiR levels such as the AChE mRNA-targeting miR-132 accompanied by stress, inflammation and metabolic symptoms, whereas the inverse approach of injecting diet-fed fattened mice with antisense oligonucleotide suppressors of miR-132 reduced hepatic fat accumulation rapidly and reproducibly. Moreover, human volunteers carrying single nucleotide polymorphisms which interfere with the AChE-targeting primate-specific miR-608 show elevated trait anxiety, blood pressure and inflammation. In contrast, Alzheimer’s brains show massive miR-132 decline, accompanying modifications in alternative splicing and transcript processing; together highlighting the relevance of these studies for personalized medicine. Non-coding RNA regulators of parasympathetic functioning thus deserve special attention.

Keywords: Acetylcholine, anxiety, non-coding RNA, microRNA, mouse engineering, synthetic oligonucleotides