Protective efficacy of phosphodiesterase-1 inhibition against alpha-synuclein toxicity revealed by compound screening in LUHMES cells
α-synuclein-induced neurotoxicity is a core pathogenic event in neurodegenerative synucleinopathies such as Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs f...
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| Veröffentlicht in: | Scientific reports 2017-09, Vol.7 (1), p.11469-15, Article 11469 |
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| creator | Höllerhage, Matthias Moebius, Claudia Melms, Johannes Chiu, Wei-Hua Goebel, Joachim N. Chakroun, Tasnim Koeglsperger, Thomas Oertel, Wolfgang H. Rösler, Thomas W. Bickle, Marc Höglinger, Günter U. |
| description | α-synuclein-induced neurotoxicity is a core pathogenic event in neurodegenerative synucleinopathies such as Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs for their efficacy to protect LUHMES cells from degeneration induced by wild-type α-synuclein and identified dipyridamole, a non-selective phosphodiesterase inhibitor, as top hit. Systematic analysis of other phosphodiesterase inhibitors identified a specific phosphodiesterase 1 inhibitor as most potent to rescue from α-synuclein toxicity. Protection was mediated by an increase of cGMP and associated with the reduction of a specific α-synuclein oligomeric species. RNA interference experiments confirmed PDE1A and to a smaller extent PDE1C as molecular targets accounting for the protective efficacy. PDE1 inhibition also rescued dopaminergic neurons from wild-type α-synuclein induced degeneration in the substantia nigra of mice. In conclusion, this work identifies inhibition of PDE1A in particular as promising target for neuroprotective treatment of synucleinopathies. |
| doi_str_mv | 10.1038/s41598-017-11664-5 |
| format | Article |
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There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs for their efficacy to protect LUHMES cells from degeneration induced by wild-type α-synuclein and identified dipyridamole, a non-selective phosphodiesterase inhibitor, as top hit. Systematic analysis of other phosphodiesterase inhibitors identified a specific phosphodiesterase 1 inhibitor as most potent to rescue from α-synuclein toxicity. Protection was mediated by an increase of cGMP and associated with the reduction of a specific α-synuclein oligomeric species. RNA interference experiments confirmed PDE1A and to a smaller extent PDE1C as molecular targets accounting for the protective efficacy. PDE1 inhibition also rescued dopaminergic neurons from wild-type α-synuclein induced degeneration in the substantia nigra of mice. In conclusion, this work identifies inhibition of PDE1A in particular as promising target for neuroprotective treatment of synucleinopathies.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-017-11664-5</identifier><identifier>PMID: 28904388</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/89 ; 631/378/87 ; 64/60 ; 692/617/375/364 ; Apoptosis ; Atrophy ; Blood-brain barrier ; Ca2+/calmodulin-dependent phosphodiesterase ; Cyclic GMP ; Dementia ; Dementia disorders ; Dipyridamole ; Dopamine receptors ; Drugs ; FDA approval ; Genomes ; Humanities and Social Sciences ; Lewy bodies ; multidisciplinary ; Neurodegeneration ; Neurology ; Neuroprotection ; Neurotoxicity ; Parkinson's disease ; Phosphodiesterase ; Phosphodiesterase inhibitors ; RNA-mediated interference ; Science ; Science (multidisciplinary) ; Substantia nigra ; Synuclein ; Toxicity</subject><ispartof>Scientific reports, 2017-09, Vol.7 (1), p.11469-15, Article 11469</ispartof><rights>The Author(s) 2017</rights><rights>2017. 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There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs for their efficacy to protect LUHMES cells from degeneration induced by wild-type α-synuclein and identified dipyridamole, a non-selective phosphodiesterase inhibitor, as top hit. Systematic analysis of other phosphodiesterase inhibitors identified a specific phosphodiesterase 1 inhibitor as most potent to rescue from α-synuclein toxicity. Protection was mediated by an increase of cGMP and associated with the reduction of a specific α-synuclein oligomeric species. RNA interference experiments confirmed PDE1A and to a smaller extent PDE1C as molecular targets accounting for the protective efficacy. PDE1 inhibition also rescued dopaminergic neurons from wild-type α-synuclein induced degeneration in the substantia nigra of mice. 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efficacy of phosphodiesterase-1 inhibition against alpha-synuclein toxicity revealed by compound screening in LUHMES cells</title><author>Höllerhage, Matthias ; Moebius, Claudia ; Melms, Johannes ; Chiu, Wei-Hua ; Goebel, Joachim N. ; Chakroun, Tasnim ; Koeglsperger, Thomas ; Oertel, Wolfgang H. ; Rösler, Thomas W. ; Bickle, Marc ; Höglinger, Günter U.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-a5cd1e0b417b84f301e0a75ded0fcbec034a056fc913f5e23359748adb401fd63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13/89</topic><topic>631/378/87</topic><topic>64/60</topic><topic>692/617/375/364</topic><topic>Apoptosis</topic><topic>Atrophy</topic><topic>Blood-brain barrier</topic><topic>Ca2+/calmodulin-dependent phosphodiesterase</topic><topic>Cyclic GMP</topic><topic>Dementia</topic><topic>Dementia disorders</topic><topic>Dipyridamole</topic><topic>Dopamine 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alpha-synuclein toxicity revealed by compound screening in LUHMES cells</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-09-13</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>11469</spage><epage>15</epage><pages>11469-15</pages><artnum>11469</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>α-synuclein-induced neurotoxicity is a core pathogenic event in neurodegenerative synucleinopathies such as Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs for their efficacy to protect LUHMES cells from degeneration induced by wild-type α-synuclein and identified dipyridamole, a non-selective phosphodiesterase inhibitor, as top hit. Systematic analysis of other phosphodiesterase inhibitors identified a specific phosphodiesterase 1 inhibitor as most potent to rescue from α-synuclein toxicity. Protection was mediated by an increase of cGMP and associated with the reduction of a specific α-synuclein oligomeric species. RNA interference experiments confirmed PDE1A and to a smaller extent PDE1C as molecular targets accounting for the protective efficacy. PDE1 inhibition also rescued dopaminergic neurons from wild-type α-synuclein induced degeneration in the substantia nigra of mice. In conclusion, this work identifies inhibition of PDE1A in particular as promising target for neuroprotective treatment of synucleinopathies.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28904388</pmid><doi>10.1038/s41598-017-11664-5</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-5333-0121</orcidid><orcidid>https://orcid.org/0000-0001-7587-6187</orcidid><orcidid>https://orcid.org/0000-0002-8918-1869</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/89 631/378/87 64/60 692/617/375/364 Apoptosis Atrophy Blood-brain barrier Ca2+/calmodulin-dependent phosphodiesterase Cyclic GMP Dementia Dementia disorders Dipyridamole Dopamine receptors Drugs FDA approval Genomes Humanities and Social Sciences Lewy bodies multidisciplinary Neurodegeneration Neurology Neuroprotection Neurotoxicity Parkinson's disease Phosphodiesterase Phosphodiesterase inhibitors RNA-mediated interference Science Science (multidisciplinary) Substantia nigra Synuclein Toxicity |
| title | Protective efficacy of phosphodiesterase-1 inhibition against alpha-synuclein toxicity revealed by compound screening in LUHMES cells |
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