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

作者：Collier Timothy J; Srivastava Kinshuk R; Justman Craig; Grammatopoulous Tom; Hutter Paier Birgit; Prokesch Manuela; Havas Daniel; Rochet Jean Christophe; Liu Fang; Jock Kevin; de Oliveira Patricia; Stirtz Georgia L; Dettmer Ulf; Sortwell Caryl E; Feany Mel B; Lan**ury Peter; Lapidus Lisa; Paumier Katrina L

来源：Neurobiology of Disease, 2017, 106: 191-204.

DOI：10.1016/j.nbd.2017.07.007

• Alpha-synuclein
• Parkinson's disease
• Biophysics
• Pre-formed fibrils
• Transgenic mouse
• Transgenic Drosophila
• Antidepressants
• Nortriptyline

The pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar alpha-synuclein (alpha-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 alpha-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 alpha-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 alpha-syn pathology by directly binding to soluble, native, alpha-syn, thereby inhibiting pathological aggregation and preserving its normal functions.

• 出版日期2017-10