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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

A model for translation repression of alpha-synuclein in which its transcript interacts with an RNA repressor protein. In the classical translation repression model, Iron-regulatory protein-1 (IRP1) controls iron dependent expression of the ferritin L- and H-chains. By analogy, phenserine, posiphen and its metabolic analogs would be predicted to increase the repressor as an RNA binding protein to interact with the SNCA 5′UTR after drug treatment. This should prohibit 40S ribosome access to the 5′UTR of SNCA mRNA to lower translation.
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fig7: A model for translation repression of alpha-synuclein in which its transcript interacts with an RNA repressor protein. In the classical translation repression model, Iron-regulatory protein-1 (IRP1) controls iron dependent expression of the ferritin L- and H-chains. By analogy, phenserine, posiphen and its metabolic analogs would be predicted to increase the repressor as an RNA binding protein to interact with the SNCA 5′UTR after drug treatment. This should prohibit 40S ribosome access to the 5′UTR of SNCA mRNA to lower translation.

Mentions: Our model to be tested is shown in Figure 7. The overarching hypothesis is that the drug phenserine (anticholinesterase) and its enantiomer are known translation blockers of the amyloid precursor protein of Alzheimer's disease (AD) and, as such, have been tested in clinical trials for their antiamyloid efficacy and potential to improve cognition. We noted that the RNA target in the 5′UTR of APP mRNA was similar to that found in the alpha-synuclein transcript. Therefore, we decided to see if posiphen and phenserine might block  α-synuclein, the central culprit protein in PD. To achieve this end, we conducted Western Blot experiments firstly with SH-SY5Y dopaminergic neuroblastoma cells and then with primary E18 neurons from a genomic mouse model of PD. Our rationale for conducting this study was to determine if posiphen and phenserine are two 5′UTR-directed drugs that would reduce alpha-synuclein expression to provide therapeutic benefit to Parkinson's disease patients.


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)

A model for translation repression of alpha-synuclein in which its transcript interacts with an RNA repressor protein. In the classical translation repression model, Iron-regulatory protein-1 (IRP1) controls iron dependent expression of the ferritin L- and H-chains. By analogy, phenserine, posiphen and its metabolic analogs would be predicted to increase the repressor as an RNA binding protein to interact with the SNCA 5′UTR after drug treatment. This should prohibit 40S ribosome access to the 5′UTR of SNCA mRNA to lower translation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: A model for translation repression of alpha-synuclein in which its transcript interacts with an RNA repressor protein. In the classical translation repression model, Iron-regulatory protein-1 (IRP1) controls iron dependent expression of the ferritin L- and H-chains. By analogy, phenserine, posiphen and its metabolic analogs would be predicted to increase the repressor as an RNA binding protein to interact with the SNCA 5′UTR after drug treatment. This should prohibit 40S ribosome access to the 5′UTR of SNCA mRNA to lower translation.
Mentions: Our model to be tested is shown in Figure 7. The overarching hypothesis is that the drug phenserine (anticholinesterase) and its enantiomer are known translation blockers of the amyloid precursor protein of Alzheimer's disease (AD) and, as such, have been tested in clinical trials for their antiamyloid efficacy and potential to improve cognition. We noted that the RNA target in the 5′UTR of APP mRNA was similar to that found in the alpha-synuclein transcript. Therefore, we decided to see if posiphen and phenserine might block  α-synuclein, the central culprit protein in PD. To achieve this end, we conducted Western Blot experiments firstly with SH-SY5Y dopaminergic neuroblastoma cells and then with primary E18 neurons from a genomic mouse model of PD. Our rationale for conducting this study was to determine if posiphen and phenserine are two 5′UTR-directed drugs that would reduce alpha-synuclein expression to provide therapeutic benefit to Parkinson's disease patients.

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