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

Abstract

There is compelling support for limiting expression of alpha-synuclein (α-syn) in the brains of Parkinson’s disease (PD) patients. An increase ofSNCAgene copy number can genetically cause familial PD where increased dose of this pathogenic protein correlates with severity of symptoms (triplication of theSNCAgene causes dementia in PD patients). Gene promoter polymorphisms were shown to increaseα-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 neuralSNCAmRNA translation and tested for targeting via its 5′untranslated region (5′UTR) 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 neuralα-synuclein translation. Primary metabolic analogs of posiphen were, likewise, characterized using primary fetal neurons grownex vivofrom the brains of Parkinson’s transgenic mice expressing the humanSNCAgene.