Lectures L4.1 Cholinergic-mediated microRNA control of hnRNPs A/B regulates cortical alternative splicing and neural functioning Amit Berson 1 , Galit Shaltiel 1 , Shahar Barbash 1 , Yael Goll 1 , Geula Hanin 1 , Keren Ofek 1 , Maya Ketzef 2 , Yehudit Gnatek 2 , Alon Friedman 2 , Hermona Soreq 1 1 The Edmond and Lily Safra Center of Neuroscience and Institute of Life Sciences, Department of Biological Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel; 2 Zlotowski Center for Neuroscience, Department of Physiology, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel e-mail: Hermona Soreq <soreq@cc.huji.ac.il> Genetic studies link neurodegeneration to inherited errors in RNA metabolism. Here, we report cholinergic-mediated alternative splicing errors in sporadic Alzheimer’s disease (AD). AD entorhinal cortices presented impaired exon exclusions, selectively reduced hnRNP A/B splicing reg- ulators and increased levels of the hnRNP A/B-targeted miRNA-211. Supporting functional relevance, hnRNP A/B knockdown in mice induced memory and electro- corticographic impairments, dendrite and synapse loss and splicing abnormalities. In-vivo neurotoxin-mediated destruction of cholinergic neurons, but not APP or Tau mutagenesis caused cortical AD-like decrease in hnRNP A/Bs and reduced exon exclusions. Inversely, choliner- gic excitation increased hnRNP A/B levels, suppressed miR-211 and elevated the cholinergic enhancer miRNA-132 which was drastically reduced in the AD cortex. Further- more, suppressing miR-132 elevated miR-211 in primary neurons whereas miR-211 did not change miR-132. Our fndings uncover hierarchical cholinergic and miRNA-me- diated hnRNP A/B loss and consequent RNA metabolism impairments as novel targets for interference with sporadic neurodegenerative processes. L4.2 RNA in pathogenesis and experimental therapy of polyglutamine diseases A. Mykowska, A. Fiszer, M. Wojciechowska, W. J. Krzyzosiak Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland e-mail: Wlodzimierz Krzyzosiak <wlodkrzy@ibch.poznan.pl> Mutant transcripts containing expanded untranslated CUG repeats are well documented pathogenic agents in myot- onic dystrophy type 1 (DM1). The mutant RNA sequesters the MBNL1 splicing factor and causes misregulation of the alternative splicing of multiple genes that are linked to clinical symptoms of the disease. Here we show that alter- native splicing defects are also caused by translated CAG repeats present in transcripts from mutant genes implicated in spinocerebellar ataxia type 3 (SCA3) and Huntington’s disease (HD) as well as by untranslated CAG repeats. We propose that alternative splicing deregulation by mutant CAG repeats may contribute to the pathological features of polyglutamine disorders. We also demonstrate selective targeting of mutant HD transcripts, in the presence of their normal alleles and other human mRNAs containing CAG repeats, by RNA interference reagents. This selectivity may lead to promis- ing therapeutic modalities for HD and other polyglutamine disorders. Session 4: Gene expression and brain disease