Study upends common belief in what triggers Parkinson’s disease

A brand new Northwestern Medicine study challenges a standard belief in what triggers Parkinson’s disease.

Degeneration of dopaminergic neurons is widely accepted as the primary event that results in Parkinson’s. But the brand new study suggests that a dysfunction within the neuron’s synapses -; the tiny gap across which a neuron can send an impulse to a different neuron -; results in deficits in dopamine and precedes the neurodegeneration.

Parkinson’s disease affects 1% to 2% of the population and is characterised by resting tremor, rigidity and bradykinesia (slowness of movement). These motor symptoms are on account of the progressive lack of dopaminergic neurons within the midbrain.

The findings, which can be published Sept. 15 in Neuron, open a brand new avenue for therapies, the scientists said.

We showed that dopaminergic synapses turn into dysfunctional before neuronal death occurs. Based on these findings, we hypothesize that targeting dysfunctional synapses before the neurons are degenerated may represent a greater therapeutic strategy.”

Dr. Dimitri Krainc, lead writer, chair of neurology at Northwestern University Feinberg School of Medicine and director of the Simpson Querrey Center for Neurogenetics

The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have a distinct physiology and findings within the mouse neurons aren’t translatable to humans, as highlighted in Krainc’s research recently published in Science.

Northwestern scientists found that dopaminergic synapses aren’t functioning appropriately in various genetic types of Parkinson’s disease. This work, along with other recent studies by Krainc’s lab, addresses one in all the foremost gaps in the sphere: how different genes linked to Parkinson’s result in degeneration of human dopaminergic neurons.

Neuronal recycling plant

Imagine two staff in a neuronal recycling plant. It’s their job to recycle mitochondria, the energy producers of the cell, which can be too old or overworked. If the dysfunctional mitochondria remain within the cell, they could cause cellular dysfunction. The means of recycling or removing these old mitochondria is known as mitophagy. The 2 staff on this recycling process are the genes Parkin and PINK1. In a standard situation, PINK1 prompts Parkin to maneuver the old mitochondria into the trail to be recycled or disposed of.

It has been well-established that folks who carry mutations in each copies of either PINK1 or Parkin develop Parkinson’s disease due to ineffective mitophagy.

The story of two sisters whose disease helped advance Parkinson’s research

Two sisters had the misfortune of being born without the PINK1 gene, because their parents were each missing a duplicate of the critical gene. This put the sisters at high risk for Parkinson’s disease, but one sister was diagnosed at age 16, while the opposite was not diagnosed until she was 48.

The explanation for the disparity led to a very important recent discovery by Krainc and his group. The sister who was diagnosed at 16 also had partial lack of Parkin, which, by itself, shouldn’t cause Parkinson’s.

“There have to be an entire lack of Parkin to cause Parkinson’s disease. So, why did the sister with only a partial lack of Parkin get the disease greater than 30 years earlier?” Krainc asked.

Consequently, the scientists realized that Parkin has one other necessary job that had previously been unknown. The gene also functions in a distinct pathway within the synaptic terminal -; unrelated to its recycling work-; where it controls dopamine release. With this recent understanding of what went fallacious for the sister, Northwestern scientists saw a brand new opportunity to spice up Parkin and the potential to stop the degeneration of dopamine neurons.

“We discovered a brand new mechanism to activate Parkin in patient neurons,” Krainc said. “Now, we want to develop drugs that stimulate this pathway, correct synaptic dysfunction and hopefully prevent neuronal degeneration in Parkinson’s.”

The primary writer of the study is Pingping Song, research assistant professor in Krainc’s lab. Other authors are Wesley Peng, Zhong Xie, Daniel Ysselstein, Talia Krainc, Yvette Wong, Niccolò Mencacci, Jeffrey Savas, and D. James Surmeier from Northwestern and Kalle Gehring from McGill University.

The title of the article is “Parkinson’s disease linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons.”

This work was supported by National Institutes of Health grants R01NS076054, R3710 NS096241, R35 NS122257 and NS121174, all from the National Institute of Neurological Disorders and Stroke.