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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

Selectivity of posiphen to inhibit translation driven by alpha-synuclein 5′UTR sequences: a second set of transient transfection experiments in which posiphen (10 μM) selectively inhibited alpha-synuclein 5′UTR-conferred luciferase expression in SH-SY5Y neural cells (SNCA 5′UTR-positive transfectants, (N = 6)). Confirming selectivity, posiphen increased luciferase expression in pGL3-transfected SH-SY5Y cells (**pGL3-SH-SY5Y serves as an experimental control since these cells were transfected with pGL3, which is the same as the H2A construct but lacks the  α-synuclein 5′UTR).
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fig4: Selectivity of posiphen to inhibit translation driven by alpha-synuclein 5′UTR sequences: a second set of transient transfection experiments in which posiphen (10 μM) selectively inhibited alpha-synuclein 5′UTR-conferred luciferase expression in SH-SY5Y neural cells (SNCA 5′UTR-positive transfectants, (N = 6)). Confirming selectivity, posiphen increased luciferase expression in pGL3-transfected SH-SY5Y cells (**pGL3-SH-SY5Y serves as an experimental control since these cells were transfected with pGL3, which is the same as the H2A construct but lacks the  α-synuclein 5′UTR).

Mentions: After 24 hr transfection of SH-SY5Y cells in a 100 mm dish with either (i) SNCA-5′UTR-pGL3 or (ii) pGL3 parental vector, cells were then passaged into 6 wells and tested with posiphen and phenserine (15 μM = for 48 hr) as shown in Figures 3 and 4 for which dose-response assays were also conducted (not shown) [34, 50].


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)

Selectivity of posiphen to inhibit translation driven by alpha-synuclein 5′UTR sequences: a second set of transient transfection experiments in which posiphen (10 μM) selectively inhibited alpha-synuclein 5′UTR-conferred luciferase expression in SH-SY5Y neural cells (SNCA 5′UTR-positive transfectants, (N = 6)). Confirming selectivity, posiphen increased luciferase expression in pGL3-transfected SH-SY5Y cells (**pGL3-SH-SY5Y serves as an experimental control since these cells were transfected with pGL3, which is the same as the H2A construct but lacks the  α-synuclein 5′UTR).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368596&req=5

fig4: Selectivity of posiphen to inhibit translation driven by alpha-synuclein 5′UTR sequences: a second set of transient transfection experiments in which posiphen (10 μM) selectively inhibited alpha-synuclein 5′UTR-conferred luciferase expression in SH-SY5Y neural cells (SNCA 5′UTR-positive transfectants, (N = 6)). Confirming selectivity, posiphen increased luciferase expression in pGL3-transfected SH-SY5Y cells (**pGL3-SH-SY5Y serves as an experimental control since these cells were transfected with pGL3, which is the same as the H2A construct but lacks the  α-synuclein 5′UTR).
Mentions: After 24 hr transfection of SH-SY5Y cells in a 100 mm dish with either (i) SNCA-5′UTR-pGL3 or (ii) pGL3 parental vector, cells were then passaged into 6 wells and tested with posiphen and phenserine (15 μM = for 48 hr) as shown in Figures 3 and 4 for which dose-response assays were also conducted (not shown) [34, 50].

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