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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 is a stereospecific inhibitor of alpha synuclein 5′UTR-directed translation. Transient transfection assays with the SNCA-5′UTR-pGL3 construct (H2A cell line). Posiphen was a highly selective inhibitor (10 μM) of  α-synuclein 5′UTR-driven expression of a luciferase reporter gene. This stereoisomer of phenserine inhibited  α-synuclein 5′UTR-driven luciferase expression in neural cells (SNCA 5′UTR-positive transfected neural cells (N = 7)). By contrast, phenserine and the known APP-specific translation number 9 blocker did not suppress alpha synuclein 5′UTR-conferred translation in H2A cells. Phenserine and APP blocker number 9 increased SNCA 5′UTR-conferred translation. These data support the mechanism-of-action of posiphen as a highly selective blocker of alpha synuclein 5′UTR activity, whereas phenserine (same chemical structure but stereoisomer of posiphen) was previously shown selectively inhibiting translation driven by the APP 5′UTR.
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fig3: Posiphen is a stereospecific inhibitor of alpha synuclein 5′UTR-directed translation. Transient transfection assays with the SNCA-5′UTR-pGL3 construct (H2A cell line). Posiphen was a highly selective inhibitor (10 μM) of  α-synuclein 5′UTR-driven expression of a luciferase reporter gene. This stereoisomer of phenserine inhibited  α-synuclein 5′UTR-driven luciferase expression in neural cells (SNCA 5′UTR-positive transfected neural cells (N = 7)). By contrast, phenserine and the known APP-specific translation number 9 blocker did not suppress alpha synuclein 5′UTR-conferred translation in H2A cells. Phenserine and APP blocker number 9 increased SNCA 5′UTR-conferred translation. These data support the mechanism-of-action of posiphen as a highly selective blocker of alpha synuclein 5′UTR activity, whereas phenserine (same chemical structure but stereoisomer of posiphen) was previously shown selectively inhibiting translation driven by the APP 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)

Posiphen is a stereospecific inhibitor of alpha synuclein 5′UTR-directed translation. Transient transfection assays with the SNCA-5′UTR-pGL3 construct (H2A cell line). Posiphen was a highly selective inhibitor (10 μM) of  α-synuclein 5′UTR-driven expression of a luciferase reporter gene. This stereoisomer of phenserine inhibited  α-synuclein 5′UTR-driven luciferase expression in neural cells (SNCA 5′UTR-positive transfected neural cells (N = 7)). By contrast, phenserine and the known APP-specific translation number 9 blocker did not suppress alpha synuclein 5′UTR-conferred translation in H2A cells. Phenserine and APP blocker number 9 increased SNCA 5′UTR-conferred translation. These data support the mechanism-of-action of posiphen as a highly selective blocker of alpha synuclein 5′UTR activity, whereas phenserine (same chemical structure but stereoisomer of posiphen) was previously shown selectively inhibiting translation driven by the APP 5′UTR.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Posiphen is a stereospecific inhibitor of alpha synuclein 5′UTR-directed translation. Transient transfection assays with the SNCA-5′UTR-pGL3 construct (H2A cell line). Posiphen was a highly selective inhibitor (10 μM) of  α-synuclein 5′UTR-driven expression of a luciferase reporter gene. This stereoisomer of phenserine inhibited  α-synuclein 5′UTR-driven luciferase expression in neural cells (SNCA 5′UTR-positive transfected neural cells (N = 7)). By contrast, phenserine and the known APP-specific translation number 9 blocker did not suppress alpha synuclein 5′UTR-conferred translation in H2A cells. Phenserine and APP blocker number 9 increased SNCA 5′UTR-conferred translation. These data support the mechanism-of-action of posiphen as a highly selective blocker of alpha synuclein 5′UTR activity, whereas phenserine (same chemical structure but stereoisomer of posiphen) was previously shown selectively inhibiting translation driven by the APP 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