The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression
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...
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| Format: | Article |
| Language: | English |
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Wiley
2012-01-01
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| Series: | Parkinson's Disease |
| Online Access: | http://dx.doi.org/10.1155/2012/142372 |
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| author | Sohan Mikkilineni Ippolita Cantuti-Castelvetri Catherine M. Cahill Amelie Balliedier Nigel H. Greig Jack T. Rogers |
| author_facet | Sohan Mikkilineni Ippolita Cantuti-Castelvetri Catherine M. Cahill Amelie Balliedier Nigel H. Greig Jack T. Rogers |
| author_sort | Sohan Mikkilineni |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-41af956b73fe428f97ba5b7dcf1bd585 |
| institution | Kabale University |
| issn | 2090-8083 2042-0080 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Parkinson's Disease |
| spelling | doaj-art-41af956b73fe428f97ba5b7dcf1bd5852025-08-20T03:55:40ZengWileyParkinson's Disease2090-80832042-00802012-01-01201210.1155/2012/142372142372The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein ExpressionSohan Mikkilineni0Ippolita Cantuti-Castelvetri1Catherine M. Cahill2Amelie Balliedier3Nigel H. Greig4Jack T. Rogers5Neurochemistry Laboratory, Massachusetts General Hospital (East), CNY2, 149, 13th Street, Charlestown, MA 02129, USAMIND, Massachusetts General Hospital, Charlestown, MA 02129, USANeurochemistry Laboratory, Massachusetts General Hospital (East), CNY2, 149, 13th Street, Charlestown, MA 02129, USANeurochemistry Laboratory, Massachusetts General Hospital (East), CNY2, 149, 13th Street, Charlestown, MA 02129, USADrug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USANeurochemistry Laboratory, Massachusetts General Hospital (East), CNY2, 149, 13th Street, Charlestown, MA 02129, USAThere 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.http://dx.doi.org/10.1155/2012/142372 |
| spellingShingle | Sohan Mikkilineni Ippolita Cantuti-Castelvetri Catherine M. Cahill Amelie Balliedier Nigel H. Greig Jack T. Rogers The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression Parkinson's Disease |
| title | The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression |
| title_full | The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression |
| title_fullStr | The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression |
| title_full_unstemmed | The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression |
| title_short | The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression |
| title_sort | anticholinesterase phenserine and its enantiomer posiphen as 5 untranslated region directed translation blockers of the parkinson s alpha synuclein expression |
| url | http://dx.doi.org/10.1155/2012/142372 |
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