Summary: Researchers report that a long-established antidepressant may slow progression of Parkinson’s disease by blocking the aggregation of alpha-synuclein proteins.
Longstanding Antidepressant Shows Early Potential to Slow Parkinson’s Progression
Michigan State University researchers have produced early evidence that nortriptyline, an antidepressant used for more than five decades, could slow the progression of Parkinson’s disease. In a proof-of-concept study published in Neurobiology of Disease, the team found that nortriptyline reduced the formation of abnormal alpha-synuclein protein aggregates linked to nerve cell death in Parkinson’s.
Researchers began by examining patient records to see whether people taking antidepressants had delayed need for levodopa, the standard therapy for Parkinson’s symptoms. Levodopa increases dopamine levels in the brain and helps control tremor and impaired movement. “Depression is a very frequent condition associated with Parkinson’s, so we became interested in whether an antidepressant could modify how the disease progresses,” said Tim Collier, lead author of the federally funded study and a neuroscientist at MSU.
The analysis suggested that patients who had been taking tricyclic antidepressants, the class that includes nortriptyline, required levodopa treatment significantly later than those who had not taken that class of medication. To follow up, Collier and colleagues tested nortriptyline in animal and laboratory models.
In rat models, nortriptyline reduced the accumulation of alpha-synuclein, a protein that can misfold and aggregate into toxic clumps that are a hallmark of Parkinson’s disease. When alpha-synuclein clusters, it can contribute to neuronal dysfunction and cell death. The MSU team reports that nortriptyline appears to interrupt that aggregation process.
Lisa Lapidus, a physics and astronomy professor and co-author, used biochemical assays to study how nortriptyline interacts with alpha-synuclein at the molecular level. “Proteins are constantly moving and changing shape,” Lapidus explained. In test-tube experiments, adding nortriptyline accelerated the reconfiguration of monomeric alpha-synuclein, keeping the protein in forms less prone to clump. This change in how fast the protein reshapes itself appears to prevent the formation of the toxic, aggregated conformations linked to neurodegeneration.
These combined findings—from patient data, animal studies and molecular assays—support the idea that nortriptyline binds to the soluble monomeric form of alpha-synuclein and enhances its dynamic reconfiguration, thereby inhibiting pathological aggregation. Because nortriptyline is already an FDA-approved, well-studied medication with a known safety profile, the researchers say it could represent a more straightforward strategy for targeting disease mechanisms rather than only treating symptoms.
Next Steps Toward Clinical Testing
Tim Collier is seeking funding to advance this work and hopes to lead a human clinical trial to evaluate whether nortriptyline can slow Parkinson’s progression in people. The research was supported by the National Institutes of Health and foundations including the Michael J. Fox Foundation and St. Mary’s Foundation.
Funding: National Institutes of Health, Michael J. Fox Foundation, St. Mary’s Foundation.
Source: Michigan State University, reporting by Sarina Gleason.
Original research: “Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form” by Timothy J. Collier et al., published in Neurobiology of Disease (online July 12, 2017). The study reports that nortriptyline directly binds soluble alpha-synuclein, enhances monomer reconfiguration, and inhibits formation of toxic fibrillar aggregates in vitro and in multiple cell and animal models.
Abstract (Summary)
Parkinson’s disease and related synucleinopathies are defined by intracellular inclusions mainly composed of misfolded, fibrillar alpha-synuclein. Preventing misfolding and aggregation of the native monomeric form is one strategy to slow disease progression. The findings reported here indicate that the tricyclic antidepressant nortriptyline (NOR) inhibits alpha-synuclein aggregation by binding the soluble monomer and enhancing monomer reconfiguration, thus reducing formation of toxic protein conformations. NOR also decreased alpha-synuclein accumulation, aggregation and neurotoxicity in multiple cell and animal models. These results suggest that nortriptyline, a medication with established clinical use, may have disease-modifying potential by directly limiting pathological alpha-synuclein aggregation while preserving normal protein function.