Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form
The pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar α-synuclein (α-syn). One strategy to slow disease progression is to prevent the misfolding and aggregation of its native mon...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-10-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996117301596 |
| _version_ | 1818725000876654592 |
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| author | Timothy J. Collier Kinshuk R. Srivastava Craig Justman Tom Grammatopoulous Birgit Hutter-Paier Manuela Prokesch Daniel Havas Jean-Christophe Rochet Fang Liu Kevin Jock Patrícia de Oliveira Georgia L. Stirtz Ulf Dettmer Caryl E. Sortwell Mel B. Feany Peter Lansbury Lisa Lapidus Katrina L. Paumier |
| author_facet | Timothy J. Collier Kinshuk R. Srivastava Craig Justman Tom Grammatopoulous Birgit Hutter-Paier Manuela Prokesch Daniel Havas Jean-Christophe Rochet Fang Liu Kevin Jock Patrícia de Oliveira Georgia L. Stirtz Ulf Dettmer Caryl E. Sortwell Mel B. Feany Peter Lansbury Lisa Lapidus Katrina L. Paumier |
| author_sort | Timothy J. Collier |
| collection | DOAJ |
| description | The pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar α-synuclein (α-syn). One strategy to slow disease progression is to prevent the misfolding and aggregation of its native monomeric form. Here we present findings that support the contention that the tricyclic antidepressant compound nortriptyline (NOR) has disease-modifying potential for synucleinopathies. Findings from in vitro aggregation and kinetics assays support the view that NOR inhibits aggregation of α-syn by directly binding to the soluble, monomeric form, and by enhancing reconfiguration of the monomer, inhibits formation of toxic conformations of the protein. We go on to demonstrate that NOR inhibits the accumulation, aggregation and neurotoxicity of α-syn in multiple cell and animal models. These findings suggest that NOR, a compound with established safety and efficacy for treatment of depression, may slow progression of α-syn pathology by directly binding to soluble, native, α-syn, thereby inhibiting pathological aggregation and preserving its normal functions. |
| first_indexed | 2024-12-17T21:35:21Z |
| format | Article |
| id | doaj.art-416c1a4af85442e1a86a6af150c46583 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T21:35:21Z |
| publishDate | 2017-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-416c1a4af85442e1a86a6af150c465832022-12-21T21:31:46ZengElsevierNeurobiology of Disease1095-953X2017-10-01106191204Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric formTimothy J. Collier0Kinshuk R. Srivastava1Craig Justman2Tom Grammatopoulous3Birgit Hutter-Paier4Manuela Prokesch5Daniel Havas6Jean-Christophe Rochet7Fang Liu8Kevin Jock9Patrícia de Oliveira10Georgia L. Stirtz11Ulf Dettmer12Caryl E. Sortwell13Mel B. Feany14Peter Lansbury15Lisa Lapidus16Katrina L. Paumier17Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Center, Grand Rapids, MI, USA; Corresponding author at: Michigan State University/College of Human Medicine, Department of Translational Science & Molecular Medicine, 333 Bostwick Ave. NE, Grand Rapids, MI 49503, USA.Department of Physics and Astronomy, Michigan State University, East Lansing, MI, USALysosomal Therapeutics, Inc., Cambridge, MA, USABioEnergetics, Boston, MA, USAQPS Research, Graz, AustriaQPS Research, Graz, AustriaQPS Research, Graz, AustriaDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USADepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USADepartment of Physics and Astronomy, Michigan State University, East Lansing, MI, USADepartment of Physics and Astronomy, Michigan State University, East Lansing, MI, USAAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Center, Grand Rapids, MI, USADepartment of Pathology, Brigham and Women's Hospital, Boston, MA, USALysosomal Therapeutics, Inc., Cambridge, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USADepartment of Physics and Astronomy, Michigan State University, East Lansing, MI, USADepartment of Neurology, Washington University, Saint Louis, MO, USAThe pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar α-synuclein (α-syn). One strategy to slow disease progression is to prevent the misfolding and aggregation of its native monomeric form. Here we present findings that support the contention that the tricyclic antidepressant compound nortriptyline (NOR) has disease-modifying potential for synucleinopathies. Findings from in vitro aggregation and kinetics assays support the view that NOR inhibits aggregation of α-syn by directly binding to the soluble, monomeric form, and by enhancing reconfiguration of the monomer, inhibits formation of toxic conformations of the protein. We go on to demonstrate that NOR inhibits the accumulation, aggregation and neurotoxicity of α-syn in multiple cell and animal models. These findings suggest that NOR, a compound with established safety and efficacy for treatment of depression, may slow progression of α-syn pathology by directly binding to soluble, native, α-syn, thereby inhibiting pathological aggregation and preserving its normal functions.http://www.sciencedirect.com/science/article/pii/S0969996117301596Alpha-synucleinParkinson's diseaseBiophysicsPre-formed fibrilsTransgenic mouseTransgenic Drosophila |
| spellingShingle | Timothy J. Collier Kinshuk R. Srivastava Craig Justman Tom Grammatopoulous Birgit Hutter-Paier Manuela Prokesch Daniel Havas Jean-Christophe Rochet Fang Liu Kevin Jock Patrícia de Oliveira Georgia L. Stirtz Ulf Dettmer Caryl E. Sortwell Mel B. Feany Peter Lansbury Lisa Lapidus Katrina L. Paumier Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form Neurobiology of Disease Alpha-synuclein Parkinson's disease Biophysics Pre-formed fibrils Transgenic mouse Transgenic Drosophila |
| title | Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form |
| title_full | Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form |
| title_fullStr | Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form |
| title_full_unstemmed | Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form |
| title_short | Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form |
| title_sort | nortriptyline inhibits aggregation and neurotoxicity of alpha synuclein by enhancing reconfiguration of the monomeric form |
| topic | Alpha-synuclein Parkinson's disease Biophysics Pre-formed fibrils Transgenic mouse Transgenic Drosophila |
| url | http://www.sciencedirect.com/science/article/pii/S0969996117301596 |
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