Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form

Neurobiology of Disease

卷:106

Craig Justman¹  Katrina L. Paumier²  Kinshuk R. Srivastava²  Tom Grammatopoulous³  Mel B. Feany⁴  Peter Lansbury⁴  Daniel Havas⁵  Georgia L. Stirtz⁶  Patrícia de Oliveira⁶  Ulf Dettmer⁷  Birgit Hutter-Paier⁷  Caryl E. Sortwell⁷  Lisa Lapidus⁸  Timothy J. Collier⁸  Manuela Prokesch⁹  Jean-Christophe Rochet¹⁰  Kevin Jock¹⁰  Fang Liu¹⁰ 

[1] Corresponding author at: Michigan State University/College of Human Medicine, Department of Translational Science &

[2] Mercy Health Hauenstein Neuroscience Center, Grand Rapids, MI, USA;

[3] Molecular Medicine, 333 Bostwick Ave. NE, Grand Rapids, MI 49503, USA.;

[4] Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA;

[5] BioEnergetics, Boston, MA, USA;

[6] Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA;

[7] Department of Physics and Astronomy, Michigan State University, East Lansing, MI, USA;

[8] Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA;

[9] Lysosomal Therapeutics, Inc., Cambridge, MA, USA;

[10] QPS Research, Graz, Austria;

关键词: Alpha-synuclein;    Parkinson's disease;    Biophysics;    Pre-formed fibrils;    Transgenic mouse;    Transgenic Drosophila;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown