Journal of Neural Transmission

, Volume 118, Issue 3, pp 493–507

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

  • Jack T. Rogers
  • Sohan Mikkilineni
  • Ippolita Cantuti-Castelvetri
  • Deborah H. Smith
  • Xudong Huang
  • Sanghamitra Bandyopadhyay
  • Catherine M. Cahill
  • Maria L. Maccecchini
  • Debomoy K. Lahiri
  • Nigel H. Greig
Basic Neurosciences, Genetics and Immunology - Original Article


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.


Parkinson’s disease Alpha-synuclein 5′untranslated region Transfection-based screen Natural product Translation blockers Amyloid precursor protein Posiphen Phenserine 


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Copyright information

© Springer-Verlag (Outside the USA) 2011

Authors and Affiliations

  • Jack T. Rogers
    • 1
  • Sohan Mikkilineni
    • 1
  • Ippolita Cantuti-Castelvetri
    • 1
    • 2
  • Deborah H. Smith
    • 3
  • Xudong Huang
    • 1
  • Sanghamitra Bandyopadhyay
    • 4
  • Catherine M. Cahill
    • 1
  • Maria L. Maccecchini
    • 5
  • Debomoy K. Lahiri
    • 6
  • Nigel H. Greig
    • 7
  1. 1.Neurochemistry Laboratory, Psychiatry-NeuroscienceMassachusetts General HospitalCharlestownUSA
  2. 2.MassGeneral Institute for Neurodegenerative Disease (MIND), Massachusetts General HospitalCharlestownUSA
  3. 3.Yale UniversityNew HavenUSA
  4. 4.Indian Institute of Toxicology Research (CSIR)LucknowIndia
  5. 5.QR Pharma Inc.RadnorUSA
  6. 6.Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric ResearchIndiana University School of MedicineINUSA
  7. 7.Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research ProgramNational Institute on AgingBaltimoreUSA

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