The difficult work of trying to understand Parkinson's disease continues, with a new study showing that the condition might be triggered earlier than had previously been thought.

Researchers from the US and Canada analyzed neurons from patients with Parkinson's, discovering a previously unknown culprit for symptoms of the disease that may begin before any of the others.

This trigger is a malfunction in the synapses (or connections) between neurons that manage dopamine production, subsequently leading to a toxic buildup of the chemical that can then cause the dopaminergic neuron damage that characterizes Parkinson's.

"We showed that dopaminergic synapses become dysfunctional before neuronal death occurs," says neuroscientist Dimitri Krainc, from Northwestern University in the US.

"Based on these findings, we hypothesize that targeting dysfunctional synapses before the neurons are degenerated may represent a better therapeutic strategy."

Neuron scans
Scientists studied neuron and synapse damage in Parkinson's patients. (Song et al., Neuron, 2023)

The existing consensus is that problems in the way worn-out mitochondria are recycled in the brain – a process technically known as mitophagy – is causing the neuron loss that leads to Parkinson's and the symptoms (such as trembling) associated with it.

Two genes, Parkin and PINK1, are responsible for mitophagy, and it's previously been established that mutations in these genes that prevent them from doing their jobs properly mean a much higher risk of developing Parkinson's.

The new research adds to this knowledge by highlighting mutations in Parkin as being responsible for dysfunction in the synapses specifically. It's a mechanism we didn't know about before, and it seems to be the earliest sign yet of Parkinson's taking hold.

It also teaches researchers more about how Parkin and PINK1 operate independently from each other.

Included in the samples were neurons from two sisters with Parkinson's. While both were born without the PINK1 gene, only one of them was completely missing the Parkin gene, which meant the diagnosis of the disease was something of a mystery.

"There must be a complete loss of Parkin to cause Parkinson's disease," Krainc says. "So, why did the sister with only a partial loss of Parkin get the disease more than 30 years earlier?

That mystery is explained by Parkin's previously unknown function in controlling dopamine release through synapses, aside from the work it also does in neuron recycling. Further down the line, we may be able to control it.

More than 10 million people worldwide are living with Parkinson's disease, with 90,000 diagnoses in the US alone every year. Those numbers are expected to increase as populations across the globe keep aging.

Both the discovery of the mechanism and its appearance in the brain before any other potential triggers are going to be crucial in the ongoing pursuit of treatments for Parkinson's disease, the researchers say.

"Now, we need to develop drugs," says Krainc, "that stimulate this pathway, correct synaptic dysfunction and hopefully prevent neuronal degeneration in Parkinson's."

The research has been published in Neuron.