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Parkinson’s Disease
Volume 2012, Article ID 142372, 13 pages
Research Article

The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression

1Neurochemistry Laboratory, Massachusetts General Hospital (East), CNY2, 149, 13th Street, Charlestown, MA 02129, USA
2MIND, Massachusetts General Hospital, Charlestown, MA 02129, USA
3Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA

Received 1 July 2011; Accepted 29 February 2012

Academic Editor: Paul S. Foster

Copyright © 2012 Sohan Mikkilineni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


There is compelling support for limiting expression of alpha-synuclein (α-syn) in the brains of Parkinson’s disease (PD) patients. An increase of SNCA gene copy number can genetically cause familial PD where increased dose of this pathogenic protein correlates with severity of symptoms (triplication of the SNCA gene causes dementia in PD patients). Gene promoter polymorphisms were shown to increase α-synuclein expression as a risk for PD. Cholinesterase inhibitors can clinically slow cognitive decline in the later stages of PD etiology similar to their widespread use in Alzheimer’s disease (AD). Pertinent to this, we identified that the well-tolerated anticholinesterase, phenserine, blocked neural SNCA mRNA translation and tested for targeting via its 5untranslated region (5UTR) in a manner similar to its action to limit the expression of the AD-specific amyloid precursor protein (APP). Posiphen, its better-tolerated (+) enantiomer (devoid of anticholinesterase action), repressed neural α-synuclein translation. Primary metabolic analogs of posiphen were, likewise, characterized using primary fetal neurons grown ex vivo from the brains of Parkinson’s transgenic mice expressing the human SNCA gene.