Alpha-synuclein is a protein that’s abundant in the brain. In healthy brain neurons, alpha-synuclein is found around the inside edges of the cell and in the tips of the synapses that pass messages to the next neuron.
We don’t understand all the functions of alpha-synuclein yet, but we do know that it’s involved in the release of dopamine. This is a crucial neurotransmitter that has a central role in the control of movement. The loss of dopamine neurons is a major feature of Parkinson’s.
In their research, a biotech company had seen in dishes in the lab, that the tricyclic antidepressant nortriptyline slowed the toxic clustering of alpha-synuclein. Professor Collier and Dr Paumier who were researching nortriptyline, confirmed this.
They also went on to show that in cells in the lab, nortriptyline prevented clusters of alpha-synuclein forming, and preserved neurons in the brain.
In Parkinson’s, alpha-synuclein proteins start bunching together and they create long structures called fibrils, which then clump together in clusters that we call Lewy bodies. The contribution of alpha-synuclein and Lewy bodies to Parkinson’s is not yet clear. However, drugs that prevent this abnormal behaviour of alpha-synuclein are of huge interest in research towards a cure for Parkinson’s.
Professor Collier and his team found that in test tube conditions, nortriptyline binds to alpha-synuclein and stops it from clustering. They then grew dopamine neurons which had very high levels of a faulty form of alpha-synuclein. This version of the protein normally kills the cells, but fewer died if they were treated with nortriptyline. Next, they fed nortriptyline to fruit flies and mice with Parkinson’s-like brains, and found reduced neurodegeneration and less accumulation of alpha-synuclein. In a further study, they have shown that a six-week course of nortriptyline in rats can prevent accumulations of alpha-synuclein in the brain, following injection with alpha-synuclein fibrils.