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The alpha-synuclein 5′untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

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 (~1 μM 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.

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References

  • Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152(4):879–884

    PubMed  CAS  Google Scholar 

  • Banati RB, Daniel SE, Blunt SB (1998) Glial pathology but absence of apoptotic nigral neurons in long- standing Parkinson’s disease [see comments]. Mov Disord 13(2):221–227

    Article  PubMed  CAS  Google Scholar 

  • Bandyopadhyay S, Huang X, Cho H, Greig NH, Youdim MB, Rogers JT (2006a) Metal specificity of an iron-responsive element in Alzheimer’s APP mRNA 5′untranslated region, tolerance of SH-SY5Y and H4 neural cells to desferrioxamine, clioquinol, VK-28, and a piperazine chelator. J Neural Transm Suppl 71:237–247

    Google Scholar 

  • Bandyopadhyay S, Ni J, Ruggiero A, Walshe K, Rogers MS, Chattopadhyay N, Glicksman MA, Rogers JT (2006b) A high-throughput drug screen targeted to the 5′untranslated region of Alzheimer amyloid precursor protein mRNA. J Biomol Screen 11(5):469–480

    Article  PubMed  CAS  Google Scholar 

  • Braak H, Rub U, Del Tredici K (2003) Involvement of precerebellar nuclei in multiple system atrophy. Neuropathol Appl Neurobiol 29(1):60–76

    Article  PubMed  CAS  Google Scholar 

  • Braak H, Rub U, Del Tredici K (2006) Cognitive decline correlates with neuropathological stage in Parkinson’s disease. J Neurol Sci 248:255–258

    Google Scholar 

  • Cabin DE, Gispert-Sanchez S, Murphy D, Auburger G, Myers RR, Nussbaum RL (2005) Exacerbated synucleinopathy in mice expressing A53T SNCA on a Snca null background. Neurobiol Aging 26(1):25–35

    Article  PubMed  CAS  Google Scholar 

  • Cahill CM, Rogers JT (2008) Interleukin-1beta induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase dependent AKT/Ikappa B kinase alpha pathway targeting activator protein-1. J Biol Chem 283:212–259

    Article  Google Scholar 

  • Cahill CM, Lahiri DK, Huang X, Rogers JT (2009) Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases. Biochim Biophys Acta 1790(7):615–628

    PubMed  CAS  Google Scholar 

  • Campbell BC, McLean CA, Culvenor JG, Gai WP, Blumbergs PC, Jakala P, Beyreuther K, Masters CL, Li QX (2001) The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J Neurochem 76(1):87–96

    Article  PubMed  CAS  Google Scholar 

  • Cantuti-Castelvetri I, Klucken J, Ingelsson M, Ramasamy K, McLean PJ, Frosch MP, Hyman BT, Standaert DG (2005) Alpha-synuclein and chaperones in dementia with Lewy bodies. J Neuropathol Exp Neurol 64(12):1058–1066

    Article  PubMed  CAS  Google Scholar 

  • Cho HH, Cahill CM, Vanderburg CR, Scherzer CR, Wang B, Huang X, Rogers JT (2010) Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1. J Biol Chem 285:31217–31232

    Google Scholar 

  • Conway KA, Harper JD, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 4(11):1318–1320

    Article  PubMed  CAS  Google Scholar 

  • Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R (2002) Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA 99:14524–14529

    Google Scholar 

  • Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI (2010) Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell 142(6):857–867

    Article  PubMed  CAS  Google Scholar 

  • Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55(3):259–272

    Article  PubMed  CAS  Google Scholar 

  • Friedlich AL, Tanzi RE, Rogers JT (2007) The 5′-untranslated region of Parkinson’s disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol Psychiatry 12(3):222–223

    Article  PubMed  CAS  Google Scholar 

  • Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2(7):492–501

    Article  PubMed  CAS  Google Scholar 

  • Goforth JB, Anderson SA, Nizzi CP, Eisenstein RS (2010) Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy. RNA 16(1):154–169

    Article  PubMed  CAS  Google Scholar 

  • Greig NH, Pei X, Soncrant TT, Ingram DK, Brossi A (1995) Phenserine and ring C hetero-analogues: drug candidates for the treatment of Alzheimer’s disease. Med Res Rev 15(1):3–31

    Article  PubMed  CAS  Google Scholar 

  • Greig NH, DeMicheli E, Utsuki T, Holloway HW, Yu QS, Perry T, Brossi A, Deutsch J, Ingram DK, Lahiri DK, Soncrant T (2000) The experimental Alzheimer drug phenserine: pharmacodynamics and kinetics in the rat. Acta Neurol Scand 102:74–84

    Article  Google Scholar 

  • Greig NH, Sambamurti K, Yu QS, Brossi A, Bruinsma GB, Lahiri DK (2005) An overview of phenserine tartrate, a novel acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease. Curr Alzheimer Res 2(3):281–290

    Article  PubMed  CAS  Google Scholar 

  • Griffaut B, Bos R, Maurizis JC, Madelmont JC, Ledoigt G (2004) Cytotoxic effects of kinetin riboside on mouse, human and plant tumour cells. Int J Biol Macromol 34(4):271–275

    Article  PubMed  CAS  Google Scholar 

  • Gunshin H, Allerson CR, Polycarpou-Schwarz M, Rofts A, Rogers JT, Kishi F, Hentze MW, Rouault TA, Andrews NC, Hediger MA (2001) Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett 509(2):309–316

    Article  PubMed  CAS  Google Scholar 

  • Hamy F, Felder ER, Heizmann G, Lazdins J, Aboul-ela F, Varani G, Karn J, Klimkait T (1997) An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication. Proc Natl Acad Sci USA 94(8):3548–3553

    Article  PubMed  CAS  Google Scholar 

  • Howe AY, Bloom J, Baldick CJ, Benetatos CA, Cheng H, Christensen JS, Chunduru SK, Coburn GA, Feld B, Gopalsamy A, Gorczyca WP, Herrmann S, Johann S, Jiang X, Kimberland ML, Krisnamurthy G, Olson M, Orlowski M, Swanberg S, Thompson I, Thorn M, Del Vecchio A, Young DC, van Zeijl M, Ellingboe JW, Upeslacis J, Collett M, Mansour TS, O’Connell JF (2004) Novel nonnucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase. Antimicrob Agents Chemother 48(12):4813–4821

    Article  PubMed  CAS  Google Scholar 

  • Irizarry MC, Growdon W, Gomez-Isla T, Newell K, George JM, Clayton DF, Hyman BT (1998) Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson’s disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. J Neuropathol Exp Neurol 57(4):334–337

    Article  PubMed  CAS  Google Scholar 

  • Kruger R, Muller T, Riess O (2000) Involvement of alpha-synuclein in Parkinson’s disease and other neurodegenerative disorders. J Neural Transm 107(1):31–40

    Article  PubMed  CAS  Google Scholar 

  • Lahiri DK, Chen D, Vivien D, Ge Y-W, Greig NH, Rogers JT (2003) Role of cytokines in the gene expression of amyloid ß-protein precursor: identification of a 5′-UTR-binding nuclear factor and its implications in Alzheimer’s disease. J Alzheimer’s Dis 5(2):81–90

    CAS  Google Scholar 

  • Lahiri DK, Ge Y-W, Maloney B (2005) Characterization of the APP proximal promoter and 5′-untranslated regions: Identification of cell type specific domains and implications in APP gene expression and Alzheimer’s disease. FASEB J 19(6):653–655

    PubMed  CAS  Google Scholar 

  • Lahiri DK, Alley GM, Tweedie D, Chen D, Greig NH (2007a) Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer’s disease. Neuromolecular Med 9(2):157–168

    Article  PubMed  CAS  Google Scholar 

  • Lahiri DK, Chen D, Maloney B, Holloway HW, Yu QS, Utsuki T, Giordano T, Sambamurti K, Greig NH (2007b) The experimental Alzheimer’s disease drug Posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice. J Pharmacol Exp Ther 320(1):386–396

    Article  PubMed  CAS  Google Scholar 

  • Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418(6895):291

    Article  PubMed  CAS  Google Scholar 

  • Lewis JA (2009) Digoxin blocks tumor growth through HIF-1alpha inhibition. Curr Top Med Chem 9(1):117

    Article  PubMed  CAS  Google Scholar 

  • Li W, West N, Colla E, Pletnikova O, Troncoso JC, Marsh L, Dawson TM, Jakala P, Hartmann T, Price DL, Lee MK (2005) Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc Natl Acad Sci USA 102(6):2162–2167

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Chen H, Huang X, Costa M (2006) Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1alpha) and HIF-regulated genes. Toxicol Appl Pharmacol 213(3):245–255

    Article  PubMed  CAS  Google Scholar 

  • Lowe R, Pountney DL, Jensen PH, Gai WP, Voelcker NH (2004) Calcium(II) selectively induces alpha-synuclein annular oligomers via interaction with the C-terminal domain. Protein Sci 13(12):3245–3252

    Article  PubMed  CAS  Google Scholar 

  • Maccecchini ML (2010) Posiphen’s pharmacokinetics and mechanism of action in mild cognitive impaired patients. Alzheimer’s & Dementia 6(4S1):e54

    Google Scholar 

  • Maccecchini ML, Roffman M, Greig NH (2009) Posiphen lowers amyloid precursor protein and amyloid β as well as acetylcholinesterase levels in culture, animals and humans. Alzheimer’s & Dementia 5(4S):47–48

    Google Scholar 

  • Malina A, Khan S, Carlson CB, Svitkin Y, Harvey I, Sonenberg N, Beal PA, Pelletier J (2005) Inhibitory properties of nucleic acid-binding ligands on protein synthesis. FEBS Lett 579(1):79–89

    Article  PubMed  CAS  Google Scholar 

  • Maloney B, Ge Y-W, Greig N, Lahiri DK (2004) Presence of a ‘CAGA box’ in the APP gene unique to amyloid plaque forming species and absent in all APLP-1/2 genes: Implications in Alzheimer’s disease. FASEB J 18(11):1288–1290

    PubMed  CAS  Google Scholar 

  • Marutle A, Ohmitsu M, Nilbratt M, Greig NH, Nordberg A, Sugaya K (2007) Modulation of human neural stem cell differentiation in APP23 transgenic mice by phenserine treatment. PNAS 104:12506–12511

    Article  PubMed  CAS  Google Scholar 

  • McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5(2):299–309

    Article  PubMed  CAS  Google Scholar 

  • Mudge DW, Atcheson B, Taylor PJ, Sturtevant JM, Hawley CM, Campbell SB, Isbel NM, Nicol DL, Pillans PI, Johnson DW (2004) The effect of oral iron admiinistration on mycophenolate mofetil absorption in renal transplant recipients: a randomized, controlled trial. Transplantation 77(2):206–209

    Article  PubMed  CAS  Google Scholar 

  • Nishioka K, Hayashi S, Farrer MJ, Singleton AB, Yoshino H, Imai H, Kitami T, Sato K, Kuroda R, Tomiyama H, Mizoguchi K, Murata M, Toda T, Imoto I, Inazawa J, Mizuno Y, Hattori N (2006) Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson’s disease. Ann Neurol 59(2):298–309

    Article  PubMed  CAS  Google Scholar 

  • Norris EH, Giasson BI, Ischiropoulos H, Lee VM (2003) Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications. J Biol Chem 278(29):27230–27240

    Article  PubMed  CAS  Google Scholar 

  • Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM (2007) Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology 68(21):1820–1825

    Article  PubMed  CAS  Google Scholar 

  • Olivares D, Huang X, Branden L, Greig NH, Rogers JT (2009) Physiological and pathological role of alpha-synuclein in Parkinson’s disease through iron mediated oxidative stress; the role of a putative iron-responsive element. Int J Mol Sci 10(3):1226–1260

    Article  PubMed  CAS  Google Scholar 

  • Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20(16):6048–6054

    PubMed  CAS  Google Scholar 

  • Payton S, Cahill CM, Randall JD, Gullans SR, Rogers JT (2003) Drug discovery targeted to the Alzheimer’s APP mRNA 5′-untranslated region: the action of paroxetine and dimercaptopropanol. J Mol Neurosci 20(3):267–275

    Article  PubMed  CAS  Google Scholar 

  • Perrin RJ, Woods WS, Clayton DF, George JM (2000) Interaction of human alpha-Synuclein and Parkinson’s disease variants with phospholipids. Structural analysis using site-directed mutagenesis. J Biol Chem 275(44):34393–34398

    Article  PubMed  CAS  Google Scholar 

  • Porse BT, Kirillov SV, Awayez MJ, Garrett RA (1999) UV-induced modifications in the peptidyl transferase loop of 23S rRNA dependent on binding of the streptogramin B antibiotic, pristinamycin IA. RNA 5(4):585–595

    Article  PubMed  CAS  Google Scholar 

  • Rogers J (2002) Pepides derived from the human amyloid precursor protein used to protect cells form iron catalyzed oxidative damage Issued US Patent WO/2002/034766

  • Rogers JT, Lahiri DK (2004) Metal andinflammatory targets for Alzheimer’s disease. Curr Drug Targets 5(6):535–551

    Article  PubMed  CAS  Google Scholar 

  • Rogers JT, Randall JD, Cahill CM, Eder PS, Huang X, Gunshin H, Leiter L, McPhee J, Sarang SS, Utsuki T, Greig NH, Lahiri DK, Tanzi RE, Bush AI, Giordano T, Gullans SR (2002a) An iron-responsive element type II in the 5′-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J Biol Chem 277(47):45518–45528

    Article  PubMed  CAS  Google Scholar 

  • Rogers JT, Randall JD, Eder PS, Huang X, Bush AI, Tanzi RE, Venti A, Payton SM, Giordano T, Nagano S, Cahill CM, Moir R, Lahiri DK, Greig N, Sarang SS, Gullans SR (2002b) Alzheimer’s disease drug discovery targeted to the APP mRNA 5′untranslated region. J Mol Neurosci 19:77–82

    Article  PubMed  CAS  Google Scholar 

  • Rogers JT, Bush AI, Cho HH, Smith DH, Thomson AM, Friedlich AL, Lahiri DK, Leedman PJ, Huang X, Cahill CM (2008) Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer’s disease. Biochem Soc Trans 36(Pt 6):1282–1287

    Article  PubMed  CAS  Google Scholar 

  • Scherzer CR, Grass JA, Liao Z, Pepivani I, Zheng B, Eklund AC, Ney PA, Ng J, McGoldrick M, Mollenhauer B, Bresnick EH, Schlossmacher MG (2008) GATA transcription factors directly regulate the Parkinson’s disease-linked gene alpha-synuclein. Proc Natl Acad Sci USA 105(31):10907–10912

    Article  PubMed  CAS  Google Scholar 

  • Shaw KT, Utsuki T, Rogers J, Yu QS, Sambamurti K, Brossi A, Ge YW, Lahiri DK, Greig NH (2001) Phenserine regulates translation of beta -amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development. Proc Natl Acad Sci USA 98(13):7605–7610

    Article  PubMed  CAS  Google Scholar 

  • Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302(5646):841

    Article  PubMed  CAS  Google Scholar 

  • Souza JM, Giasson BI, Chen Q, Lee VM, Ischiropoulos H (2000) Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J Biol Chem 275(24):18344–18349

    Article  PubMed  CAS  Google Scholar 

  • Strobel G (2009) The spectrum series: grappling with the overlap between Alzheimer’s and Parkinson’s diseases. 9th International Conference on Alzheimer’s and Parkinson’s Diseases, 11–15 March 2009, Prague, Czech Republic. J Alzheimers Dis 18(3):625–640

  • Taylor JP, Mata IF, Farrer MJ (2006) LRRK2: a common pathway for parkinsonism, pathogenesis and prevention? Trends Mol Med 12(2):76–82

    Article  PubMed  CAS  Google Scholar 

  • Thomas JR, Hergenrother PJ (2008) Targeting RNA with small molecules. Chem Rev 108(4):1171–1224

    Article  PubMed  CAS  Google Scholar 

  • Tibodeau JD, Fox PM, Ropp PA, Theil EC, Thorp HH (2006) The up-regulation of ferritin expression using a small-molecule ligand to the native mRNA. Proc Natl Acad Sci USA 103(2):253–257

    Article  PubMed  CAS  Google Scholar 

  • Toth I, Yuan L, Rogers JT, Boyce H, Bridges KR (1999) Hypoxia alters iron-regulatory protein-1 binding capacity and modulates cellular iron homeostasis in human hepatoma and erythroleukemia cells. J Biol Chem 274:4467–4473

    Google Scholar 

  • Tucker S, Ahl M, Cho HH, Bandyopadhyay S, Cuny GD, Bush AI, Goldstein LE, Westaway D, Huang X, Rogers JT (2006) RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine. Curr Alzheimer Res 3(3):221–227

    Article  PubMed  CAS  Google Scholar 

  • Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90(23):11282–11286

    Article  PubMed  CAS  Google Scholar 

  • Utsuki T, Uchimura N, Irikura M, Moriuchi H, Holloway HW, Yu QS, Spangler EL, Mamczarz J, Ingram DK, Irie T, Greig NH (2007) Preclinical investigation of the topical administration of phenserine: transdermal flux, cholinesterase inhibition, and cognitive efficacy. J Pharmacol Exp Ther 321(1):353–361

    Article  PubMed  CAS  Google Scholar 

  • Uversky VN (2007) Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 103(1):17–37

    PubMed  CAS  Google Scholar 

  • Uversky VN, Li J, Fink AL (2001a) Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson’s disease and heavy metal exposure. J Biol Chem 276(47):44284–44296

    Article  PubMed  CAS  Google Scholar 

  • Uversky VN, Li J, Fink AL (2001b) Pesticides directly accelerate the rate of alpha-synuclein fibril formation: a possible factor in Parkinson’s disease. FEBS Lett 500(3):105–108

    Article  PubMed  CAS  Google Scholar 

  • Uversky VN, Li J, Souillac P, Millett IS, Doniach S, Jakes R, Goedert M, Fink AL (2002) Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J Biol Chem 277(14):11970–11978

    Article  PubMed  CAS  Google Scholar 

  • Venti A, Giordano T, Eder P, Bush AI, Lahiri DK, Greig NH, Rogers JT (2004) The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5′-untranslated region. Ann NY Acad Sci 1035:34–48

    Article  PubMed  CAS  Google Scholar 

  • Villarroel MC, Hidalgo M, Jimeno A (2009) Mycophenolate mofetil: an update. Brugs Today (Barc) 45:521–532

    Google Scholar 

  • Wang JK, Portbury S, Thomas MB, Barney S, Ricca DJ, Morris DL, Warner DS, Lo DC (2006) Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform. Proc Natl Acad Sci USA 103(27):10461–10466

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Di X, D’Agostino RB Jr, Torti SV, Torti FM (2007) Excess capacity of the iron regulatory protein system. J Biol Chem 282(34):24650–24659

    Article  PubMed  CAS  Google Scholar 

  • Wang WW, Khajavi M, Patel BJ, Beach J, Jankovic J, Ashizawa T (1998) The G209A mutation in the alpha-synuclein gene is not detected in familial cases of Parkinson disease in non-Greek and/or Italian populations. Arch Neurol 55(12):1521–1523

    Article  PubMed  CAS  Google Scholar 

  • Werstuck G, Green MR (1998) Controlling gene expression in living cells through small molecule-RNA interactions. Science 282:296–298

    Article  PubMed  CAS  Google Scholar 

  • Winblad B, Giacobini E, Frölich L, Friedhoff L, Bruinsma G, Becker RE, Greig NH (2010) Phenserine efficacy in Alzheimer’s disease. J Alzheimer’s Dis. (in press)

  • Wingert RA, Galloway JL, Barut B, Foott H, Fraenkel P, Axe JL, Weber GJ, Dooley K, Davidson AJ, Schmid B, Paw BH, Shaw GC, Kingsley P, Palis J, Schubert H, Chen O, Kaplan J, Zon LI (2005) Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature 436(7053):1035–1039

    Article  PubMed  CAS  Google Scholar 

  • Xia Y, Saitoh T, Ueda K, Tanaka S, Chen X, Hashimoto M, Hsu L, Conrad C, Sundsmo M, Yoshimoto M, Thal L, Katzman R, Masliah E (2001) Characterization of the human alpha-synuclein gene: genomic structure, transcription start site, promoter region and polymorphisms. J Alzheimers Dis 3(5):485–494

    PubMed  Google Scholar 

  • Yamin G, Glaser CB, Uversky VN, Fink AL (2003) Certain metals trigger fibrillation of methionine-oxidized alpha-synuclein. J Biol Chem 278(30):27630–27635

    Article  PubMed  CAS  Google Scholar 

  • Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R, Dang CV, Liu JO, Semenza GL (2008) Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc Natl Acad Sci USA 105(50):19579–19586

    Article  PubMed  CAS  Google Scholar 

  • Zimmer M, Ebert BL, Neil C, Brenner K, Papaioannou I, Melas A, Tolliday N, Lamb J, Pantopoulos K, Golub T, Iliopoulos O (2008) Small-molecule inhibitors of HIF-2a translation link its 5′UTR iron-responsive element to oxygen sensing. Mol Cell 32(6):838–848

    Article  PubMed  CAS  Google Scholar 

  • Zuker M (1989) Computer prediction of RNA structure. Methods Enzymol 180:262–288

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by the Michael J. Fox Foundation Novel Drug Discoveries Award, National Institute of Aging R01 AG20181 (JTR), Alzheimer’s Association Zenith Award 09-131352 (JTR), ISOA (JTR), QR Pharma Inc. (MLM), the National Institutes of Health Grants [AG18379 and AG18884 (DKL)] and the Intramural Research Program, National Institute on Aging, National Institutes of Health (NHG). ICC was supported by the MGH/MIT Morris Udall Center of Excellence in PD Research (NIH NS38372), and the APDA Advanced Center for Parkinson Research at MGH. We are indebted for the input and support of Professor Moussa Youdim, a pioneer in the fields of Parkinson’s disease research, and an innovative drug discoverer and developer.

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Correspondence to Jack T. Rogers.

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Rogers, J.T., Mikkilineni, S., Cantuti-Castelvetri, I. et al. The alpha-synuclein 5′untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen. J Neural Transm 118, 493–507 (2011). https://doi.org/10.1007/s00702-010-0513-5

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