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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

The 5′untranslated region (5′UTR) of the Parkinson's disease alpha-synuclein (SNCA) transcript is homologous to the iron-responsive element (IRE) in H-ferritin mRNA. (a) Top panel: The SNCA 5′UTR is encoded by exon-1 and exon-2 of the SNCA gene, which can be alternatively spliced to generate either a shorter exon-1/-2 transcript or a longer exon-1′-2 transcript [58]. Bottom panel: evolutionary alignment of the SNCA 5′UTR relative to the human sequence and the CAGUGN loop/splice site sequences [33]. We quantified the homology across the SNCA splice junction in the 5′untranslated region. (b) RNA/FOLD computer program predictions of RNA stem loops from SNCA 5′UTR sequences (ΔG = 53 kcal/mol). The human SNCA stem loop resembles the classical IRE RNA stem loop (5′CAGUGN3' loop motif) that controls iron-dependent L- and H-ferritin translation and transferrin receptor (TfR) mRNA stability. Stem loops from the 5′UTRs of several species were predicted to be folded, as described in the Materials and Methods section, and the pseudotriloop AGU is depicted in red lettering at the apex of the H-ferritin IRE [59] where the analogous AGA from the APP IRE is depicted [50]. The human SNCA mRNA exhibited an AGU triloop, whereas, in lower vertebrates, this AGU motif was located in the stem regions of these transcripts. Shown are the arrangement of splice sites and 5′UTR structures in the SNCA, SNCB, SNCG mRNAs. Tabulated: the first table shows the homology between the IRE-like domains in each exon of the human alpha-synuclein compared to its counterparts in different mammalian species. The second table shows the homology between the 5′untranslated regions of SNCA with the APP and ferritin L- and H-chains. This data underscored our identification of cotranslational repression of APP and alpha-synuclein by small molecules, such as phenserine and posiphen.
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fig1: The 5′untranslated region (5′UTR) of the Parkinson's disease alpha-synuclein (SNCA) transcript is homologous to the iron-responsive element (IRE) in H-ferritin mRNA. (a) Top panel: The SNCA 5′UTR is encoded by exon-1 and exon-2 of the SNCA gene, which can be alternatively spliced to generate either a shorter exon-1/-2 transcript or a longer exon-1′-2 transcript [58]. Bottom panel: evolutionary alignment of the SNCA 5′UTR relative to the human sequence and the CAGUGN loop/splice site sequences [33]. We quantified the homology across the SNCA splice junction in the 5′untranslated region. (b) RNA/FOLD computer program predictions of RNA stem loops from SNCA 5′UTR sequences (ΔG = 53 kcal/mol). The human SNCA stem loop resembles the classical IRE RNA stem loop (5′CAGUGN3' loop motif) that controls iron-dependent L- and H-ferritin translation and transferrin receptor (TfR) mRNA stability. Stem loops from the 5′UTRs of several species were predicted to be folded, as described in the Materials and Methods section, and the pseudotriloop AGU is depicted in red lettering at the apex of the H-ferritin IRE [59] where the analogous AGA from the APP IRE is depicted [50]. The human SNCA mRNA exhibited an AGU triloop, whereas, in lower vertebrates, this AGU motif was located in the stem regions of these transcripts. Shown are the arrangement of splice sites and 5′UTR structures in the SNCA, SNCB, SNCG mRNAs. Tabulated: the first table shows the homology between the IRE-like domains in each exon of the human alpha-synuclein compared to its counterparts in different mammalian species. The second table shows the homology between the 5′untranslated regions of SNCA with the APP and ferritin L- and H-chains. This data underscored our identification of cotranslational repression of APP and alpha-synuclein by small molecules, such as phenserine and posiphen.

Mentions: In Figure 1, we performed a full bioinformatic analysis of the SNCA 5′UTR demonstrating by computer-mediated predictions [50] that the 5′UTR of the SNCA transcript folds into a unique RNA stem loop resembling an iron-responsive element (IRE) RNA structure that is related to, but distinct from, the H-ferritin and APP 5′UTR-specific IREs [33]. We are currently testing the capacity of intracellular iron chelation with desferrioxamine to repress neural  α-synuclein translation acting via the IRE in the 5′UTR of its transcript, as we reported for the APP and ferritin mRNAs [42, 51].


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)

The 5′untranslated region (5′UTR) of the Parkinson's disease alpha-synuclein (SNCA) transcript is homologous to the iron-responsive element (IRE) in H-ferritin mRNA. (a) Top panel: The SNCA 5′UTR is encoded by exon-1 and exon-2 of the SNCA gene, which can be alternatively spliced to generate either a shorter exon-1/-2 transcript or a longer exon-1′-2 transcript [58]. Bottom panel: evolutionary alignment of the SNCA 5′UTR relative to the human sequence and the CAGUGN loop/splice site sequences [33]. We quantified the homology across the SNCA splice junction in the 5′untranslated region. (b) RNA/FOLD computer program predictions of RNA stem loops from SNCA 5′UTR sequences (ΔG = 53 kcal/mol). The human SNCA stem loop resembles the classical IRE RNA stem loop (5′CAGUGN3' loop motif) that controls iron-dependent L- and H-ferritin translation and transferrin receptor (TfR) mRNA stability. Stem loops from the 5′UTRs of several species were predicted to be folded, as described in the Materials and Methods section, and the pseudotriloop AGU is depicted in red lettering at the apex of the H-ferritin IRE [59] where the analogous AGA from the APP IRE is depicted [50]. The human SNCA mRNA exhibited an AGU triloop, whereas, in lower vertebrates, this AGU motif was located in the stem regions of these transcripts. Shown are the arrangement of splice sites and 5′UTR structures in the SNCA, SNCB, SNCG mRNAs. Tabulated: the first table shows the homology between the IRE-like domains in each exon of the human alpha-synuclein compared to its counterparts in different mammalian species. The second table shows the homology between the 5′untranslated regions of SNCA with the APP and ferritin L- and H-chains. This data underscored our identification of cotranslational repression of APP and alpha-synuclein by small molecules, such as phenserine and posiphen.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: The 5′untranslated region (5′UTR) of the Parkinson's disease alpha-synuclein (SNCA) transcript is homologous to the iron-responsive element (IRE) in H-ferritin mRNA. (a) Top panel: The SNCA 5′UTR is encoded by exon-1 and exon-2 of the SNCA gene, which can be alternatively spliced to generate either a shorter exon-1/-2 transcript or a longer exon-1′-2 transcript [58]. Bottom panel: evolutionary alignment of the SNCA 5′UTR relative to the human sequence and the CAGUGN loop/splice site sequences [33]. We quantified the homology across the SNCA splice junction in the 5′untranslated region. (b) RNA/FOLD computer program predictions of RNA stem loops from SNCA 5′UTR sequences (ΔG = 53 kcal/mol). The human SNCA stem loop resembles the classical IRE RNA stem loop (5′CAGUGN3' loop motif) that controls iron-dependent L- and H-ferritin translation and transferrin receptor (TfR) mRNA stability. Stem loops from the 5′UTRs of several species were predicted to be folded, as described in the Materials and Methods section, and the pseudotriloop AGU is depicted in red lettering at the apex of the H-ferritin IRE [59] where the analogous AGA from the APP IRE is depicted [50]. The human SNCA mRNA exhibited an AGU triloop, whereas, in lower vertebrates, this AGU motif was located in the stem regions of these transcripts. Shown are the arrangement of splice sites and 5′UTR structures in the SNCA, SNCB, SNCG mRNAs. Tabulated: the first table shows the homology between the IRE-like domains in each exon of the human alpha-synuclein compared to its counterparts in different mammalian species. The second table shows the homology between the 5′untranslated regions of SNCA with the APP and ferritin L- and H-chains. This data underscored our identification of cotranslational repression of APP and alpha-synuclein by small molecules, such as phenserine and posiphen.
Mentions: In Figure 1, we performed a full bioinformatic analysis of the SNCA 5′UTR demonstrating by computer-mediated predictions [50] that the 5′UTR of the SNCA transcript folds into a unique RNA stem loop resembling an iron-responsive element (IRE) RNA structure that is related to, but distinct from, the H-ferritin and APP 5′UTR-specific IREs [33]. We are currently testing the capacity of intracellular iron chelation with desferrioxamine to repress neural  α-synuclein translation acting via the IRE in the 5′UTR of its transcript, as we reported for the APP and ferritin mRNAs [42, 51].

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