caa a22 4500 445376821 CHVBK 20180317143005.0 cr unu---uuuuu 170323e20110301xx s 000 0 eng 10.1007/s00702-010-0513-5 doi (NATIONALLICENCE)springer-10.1007/s00702-010-0513-5 The alpha-synuclein 5′untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen [Elektronische Daten] [Jack Rogers, Sohan Mikkilineni, Ippolita Cantuti-Castelvetri, Deborah Smith, Xudong Huang, Sanghamitra Bandyopadhyay, Catherine Cahill, Maria Maccecchini, Debomoy Lahiri, Nigel Greig] Increased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5′untranslated region (5′UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5′UTR, whereas, by contrast, the H-ferritin 5′UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5′UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5′UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1μM IC50) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo. Springer-Verlag (Outside the USA), 2011 Parkinson's disease nationallicence Alpha-synuclein nationallicence 5′untranslated region nationallicence Transfection-based screen nationallicence Natural product nationallicence Translation blockers nationallicence Amyloid precursor protein nationallicence Posiphen nationallicence Phenserine nationallicence Rogers Jack Neurochemistry Laboratory, Psychiatry-Neuroscience, Massachusetts General Hospital, 02129, Charlestown, MA, USA aut Mikkilineni Sohan Neurochemistry Laboratory, Psychiatry-Neuroscience, Massachusetts General Hospital, 02129, Charlestown, MA, USA aut Cantuti-Castelvetri Ippolita Neurochemistry Laboratory, Psychiatry-Neuroscience, Massachusetts General Hospital, 02129, Charlestown, MA, USA aut Smith Deborah Yale University, New Haven, CT, USA aut Huang Xudong Neurochemistry Laboratory, Psychiatry-Neuroscience, Massachusetts General Hospital, 02129, Charlestown, MA, USA aut Bandyopadhyay Sanghamitra Indian Institute of Toxicology Research (CSIR), Lucknow, India aut Cahill Catherine Neurochemistry Laboratory, Psychiatry-Neuroscience, Massachusetts General Hospital, 02129, Charlestown, MA, USA aut Maccecchini Maria QR Pharma Inc., 19087, Radnor, PA, USA aut Lahiri Debomoy Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, IN, USA aut Greig Nigel Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, 21224, Baltimore, MD, USA aut Journal of Neural Transmission Springer Vienna 118/3(2011-03-01), 493-507 0300-9564 118:3<493 2011 118 702 https://doi.org/10.1007/s00702-010-0513-5 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00702-010-0513-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Rogers Jack Neurochemistry Laboratory, Psychiatry-Neuroscience, Massachusetts General Hospital, 02129, Charlestown, MA, USA aut NATIONALLICENCE 700 1- Mikkilineni Sohan Neurochemistry Laboratory, Psychiatry-Neuroscience, Massachusetts General Hospital, 02129, Charlestown, MA, USA aut NATIONALLICENCE 700 1- Cantuti-Castelvetri Ippolita Neurochemistry Laboratory, Psychiatry-Neuroscience, Massachusetts General Hospital, 02129, Charlestown, MA, USA aut NATIONALLICENCE 700 1- Smith Deborah Yale University, New Haven, CT, USA aut NATIONALLICENCE 700 1- Huang Xudong Neurochemistry Laboratory, Psychiatry-Neuroscience, Massachusetts General Hospital, 02129, Charlestown, MA, USA aut NATIONALLICENCE 700 1- Bandyopadhyay Sanghamitra Indian Institute of Toxicology Research (CSIR), Lucknow, India aut NATIONALLICENCE 700 1- Cahill Catherine Neurochemistry Laboratory, Psychiatry-Neuroscience, Massachusetts General Hospital, 02129, Charlestown, MA, USA aut NATIONALLICENCE 700 1- Maccecchini Maria QR Pharma Inc., 19087, Radnor, PA, USA aut NATIONALLICENCE 700 1- Lahiri Debomoy Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, IN, USA aut NATIONALLICENCE 700 1- Greig Nigel Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, 21224, Baltimore, MD, USA aut NATIONALLICENCE 773 0- Journal of Neural Transmission Springer Vienna 118/3(2011-03-01), 493-507 0300-9564 118:3<493 2011 118 702 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer