Aggregates of alpha-synuclein alter the electrical activity of dopamine-producing neurons, demonstrating a mechanistic link between two key features of Parkinson’s disease, a new study reports.
Parkinson’s disease is caused by the death of dopamine-producing (dopaminergic) neurons in a part of the brain called the substantia nigra, which regulates balance and movement. Part of the reason Parkinson’s can be difficult to diagnose early is that symptoms don’t become evident until the majority of these neurons are already lost.
A key molecular feature in the brain of Parkinson’s patients is the formation of aggregates (clumps) of the protein alpha-synuclein. This protein is usually present as a monomer (single protein) in brain cells, but aggregates of alpha-synuclein are thought to have toxic effects that drive disease. However, the mechanistic connection between alpha-synuclein aggregates and dopaminergic neuron dysfunction is unclear.
In the new study, researchers at the University of Warwick, United Kingdom, performed detailed analyses of the effects of alpha-synuclein aggregates on dopaminergic neurons from mice to better understand this connection.
“By only injecting low concentrations of structurally-defined alpha synuclein aggregates into single dopaminergic neurons we can characterise early changes in neuronal function, which may occur before the clinical onset of the disease,” study co-author Emily Hill, a PhD student at the university, said in a press release.
The researchers found that alpha-synuclein aggregates significantly reduced the electrical resistance of the neurons after 32 minutes, with changes first becoming evident after about eight to 16 minutes. In contrast, alpha-synuclein monomers did not significantly change the neurons’ resistance.
The firing rate — that is, the frequency of electrical signals — of neurons injected with alpha-synuclein aggregates also was reduced after 32 minutes. Monomers of alpha-synuclein did not significantly change the firing rate.
“This fall in firing rate induced by [alpha-synuclein] aggregates is consistent with the marked fall in neuronal resistance,” the researchers wrote.
The reduction in firing rate, the researchers said, could reduce the amount of dopamine these cells release, which ultimately would be detrimental to their function.
Based on previous research, the investigators suspected that this change in resistance was linked with opening of ATP-sensitive K channels (KATP), a type of protein in the membrane of neurons that helps regulate electrical activity by controlling the movement of ions in and out of the cell.
“We then thought if we could block this channel maybe we could prevent these early toxic effects,” Hill said.
To this end, the researchers examined the effects of alpha-synuclein aggregates on neurons that had been pre-treated with glibenclamide, a KATP blocker that is used in the treatment of diabetes.
In neurons pre-treated with glibenclamide, alpha-synuclein aggregates did not significantly alter the resistance or the firing rate. Importantly, glibenclamide itself (in the absence of alpha-synuclein) did not significantly affect resistance or firing rate, suggesting that the observed effect was due to the medication blocking the activity of the protein aggregates.
Because glibenclamide is known to block KATP, the results suggest that, indeed, alpha-synuclein aggregates lead to abnormal opening of these channels in neurons, However, the researchers stressed that more studies will be needed to confirm this probable mechanism of action.
Regardless, since glibenclamide blocked the effects of alpha-synuclein aggregates on the neurons, it’s possible that this medication could be useful for treating or preventing Parkinson’s disease.
“It is possible that existing drugs could be repurposed for treating different diseases. It is known that patients treated for type two diabetes have less prevalence of Parkinson’s disease,” Hill said. “Understanding the mechanisms underlying alpha synuclein pathology in single brain neurons could lead to new therapeutic targets for Parkinson’s disease.”
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