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See 1 citation in Neurobiology Of Disease 2017 by Collier:

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

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

Author information

1
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Center, Grand Rapids, MI, USA. Electronic address: timothy.collier@hc.msu.edu.
2
Department of Physics and Astronomy, Michigan State University, East Lansing, MI, USA.
3
Lysosomal Therapeutics, Inc., Cambridge, MA, USA.
4
BioEnergetics, Boston, MA, USA.
5
QPS Research, Graz, Austria.
6
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
7
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
8
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Center, Grand Rapids, MI, USA.
9
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
10
Lysosomal Therapeutics, Inc., Cambridge, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
11
Department of Neurology, Washington University, Saint Louis, MO, USA.

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

PMID:
28711409
PMCID:
PMC5793922
DOI:
10.1016/j.nbd.2017.07.007
[Indexed for MEDLINE]
Free PMC Article

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