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The anticholinesterase phenserine and its enantiomer posiphen as 5'untranslated-region-directed translation blockers of the Parkinson's alpha synuclein expression.

Mikkilineni S, Cantuti-Castelvetri I, Cahill CM, Balliedier A, Greig NH, Rogers JT - Parkinsons Dis (2012)

Bottom Line: 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 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 neural α-synuclein translation.

View Article: PubMed Central - PubMed

Affiliation: Neurochemistry Laboratory, Massachusetts General Hospital (East), CNY2, 149, 13th Street, Charlestown, MA 02129, USA.

ABSTRACT
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 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 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.

No MeSH data available.


Related in: MedlinePlus

Posiphen and phenserine decrease both APP and  α-synuclein levels dose-dependently in dopaminergic SH-SY5Y cells. Panel A: the 5′UTRs of both the APP and SNCA genes are 50% homologous with the IRE H-ferritin mRNA. Panel B: SH-SY5Y cells were treated with concentrations ranging from 0 to 10 μM phenserine and posiphen for 48 h. Harvested cell lysates were prepared. Quantitative Western Blotting established the anti-α-syn efficacy of posiphen and phenserine (IC50 < 5 μM); after standardization for β-actin (Densitometry of multiple lanes (n = 8) by ImageQuant). Cell viability was unaffected (measured by standardized ATP levels/cell (Tm (Cell-Titer-glo, Promega, Inc.))).
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fig2: Posiphen and phenserine decrease both APP and  α-synuclein levels dose-dependently in dopaminergic SH-SY5Y cells. Panel A: the 5′UTRs of both the APP and SNCA genes are 50% homologous with the IRE H-ferritin mRNA. Panel B: SH-SY5Y cells were treated with concentrations ranging from 0 to 10 μM phenserine and posiphen for 48 h. Harvested cell lysates were prepared. Quantitative Western Blotting established the anti-α-syn efficacy of posiphen and phenserine (IC50 < 5 μM); after standardization for β-actin (Densitometry of multiple lanes (n = 8) by ImageQuant). Cell viability was unaffected (measured by standardized ATP levels/cell (Tm (Cell-Titer-glo, Promega, Inc.))).

Mentions: Furthermore, as posiphen can be effectively dosed in rodents and humans in far greater amounts than phenserine, thereby generating high levels of its primary metabolites, the three most prominent primary metabolic products of posiphen were also characterized. As a model to examine the  α-syn-lowering efficacy of these agents, we assessed the cellular therapeutic impact of these screened SNCA 5′UTR-directed translation blockers to reduce  α-synuclein expression in neural cells lines and subsequently also in the primary neurons from the PAC/Tg(SNCA) genomic human SNCA mouse model of PD (Figures 2 and 6) [48].


The anticholinesterase phenserine and its enantiomer posiphen as 5'untranslated-region-directed translation blockers of the Parkinson's alpha synuclein expression.

Mikkilineni S, Cantuti-Castelvetri I, Cahill CM, Balliedier A, Greig NH, Rogers JT - Parkinsons Dis (2012)

Posiphen and phenserine decrease both APP and  α-synuclein levels dose-dependently in dopaminergic SH-SY5Y cells. Panel A: the 5′UTRs of both the APP and SNCA genes are 50% homologous with the IRE H-ferritin mRNA. Panel B: SH-SY5Y cells were treated with concentrations ranging from 0 to 10 μM phenserine and posiphen for 48 h. Harvested cell lysates were prepared. Quantitative Western Blotting established the anti-α-syn efficacy of posiphen and phenserine (IC50 < 5 μM); after standardization for β-actin (Densitometry of multiple lanes (n = 8) by ImageQuant). Cell viability was unaffected (measured by standardized ATP levels/cell (Tm (Cell-Titer-glo, Promega, Inc.))).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Posiphen and phenserine decrease both APP and  α-synuclein levels dose-dependently in dopaminergic SH-SY5Y cells. Panel A: the 5′UTRs of both the APP and SNCA genes are 50% homologous with the IRE H-ferritin mRNA. Panel B: SH-SY5Y cells were treated with concentrations ranging from 0 to 10 μM phenserine and posiphen for 48 h. Harvested cell lysates were prepared. Quantitative Western Blotting established the anti-α-syn efficacy of posiphen and phenserine (IC50 < 5 μM); after standardization for β-actin (Densitometry of multiple lanes (n = 8) by ImageQuant). Cell viability was unaffected (measured by standardized ATP levels/cell (Tm (Cell-Titer-glo, Promega, Inc.))).
Mentions: Furthermore, as posiphen can be effectively dosed in rodents and humans in far greater amounts than phenserine, thereby generating high levels of its primary metabolites, the three most prominent primary metabolic products of posiphen were also characterized. As a model to examine the  α-syn-lowering efficacy of these agents, we assessed the cellular therapeutic impact of these screened SNCA 5′UTR-directed translation blockers to reduce  α-synuclein expression in neural cells lines and subsequently also in the primary neurons from the PAC/Tg(SNCA) genomic human SNCA mouse model of PD (Figures 2 and 6) [48].

Bottom Line: 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 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 neural α-synuclein translation.

View Article: PubMed Central - PubMed

Affiliation: Neurochemistry Laboratory, Massachusetts General Hospital (East), CNY2, 149, 13th Street, Charlestown, MA 02129, USA.

ABSTRACT
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 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 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.

No MeSH data available.


Related in: MedlinePlus