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

Neurobiol Dis. 2017 Oct;106:191-204. doi: 10.1016/j.nbd.2017.07.007. Epub 2017 Jul 12.

Abstract

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.

Keywords: Alpha-synuclein; Antidepressants; Biophysics; Nortriptyline; Parkinson's disease; Pre-formed fibrils; Transgenic Drosophila; Transgenic mouse.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Antidepressive Agents, Tricyclic / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Cell Line, Tumor
  • Drosophila
  • Escherichia coli
  • Humans
  • Male
  • Mice
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Nortriptyline / pharmacology*
  • Protein Aggregation, Pathological / drug therapy*
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / pathology
  • Protein Unfolding / drug effects
  • Random Allocation
  • Rats, Sprague-Dawley
  • Recombinant Proteins / metabolism
  • alpha-Synuclein / antagonists & inhibitors
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Antidepressive Agents, Tricyclic
  • Neuroprotective Agents
  • Recombinant Proteins
  • SNCA protein, human
  • alpha-Synuclein
  • Nortriptyline