Long Reads |

Newly discovered trigger of Parkinson's upends common beliefs

Time to read: 2 minutes, 59 seconds
 

Adapted from the original Press Release Published: 15 September 2023
 

A new Northwestern Medicine study challenges a common belief in what triggers Parkinson's disease.

Degeneration of dopaminergic neurons is widely accepted as the first event that leads to Parkinson's. However, the new study suggests that a dysfunction in the neuron's synapses -- the tiny gap across which a neuron can send an impulse to another neuron leads to deficits in dopamine and precedes the neurodegeneration.

Parkinson's disease affects 1% to 2% of the population and is characterized by resting tremor, rigidity and bradykinesia (slowness of movement). These motor symptoms are due to the progressive loss of dopaminergic neurons in the midbrain.
The findings, which will be published Sept. 15 in Neuron, open a new avenue for therapies, the scientists said.

"We showed that dopaminergic synapses become dysfunctional before neuronal death occurs," said lead author Dr. Dimitri Krainc, chair of neurology at Northwestern University Feinberg School of Medicine and director of the Simpson Querrey Center for Neurogenetics. "Based on these findings, we hypothesize that targeting dysfunctional synapses before the neurons are degenerated may represent a better therapeutic strategy."
The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have a different physiology and findings in the mouse neurons are not translatable to humans, as highlighted in Krainc's research recently published in Science.

Northwestern scientists found that dopaminergic synapses are not functioning correctly in various genetic forms of Parkinson's disease. This work, together with other recent studies by Krainc's lab, addresses one of the major gaps in the field: how different genes linked to Parkinson's lead to degeneration of human dopaminergic neurons.
 

Neuronal recycling plant

Imagine two workers in a neuronal recycling plant. It's their job to recycle mitochondria, the energy producers of the cell, that are too old or overworked. If the dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or removing these old mitochondria is called mitophagy. The two workers in this recycling process are the genes Parkin and PINK1. In a normal situation, PINK1 activates Parkin to move the old mitochondria into the path to be recycled or disposed of.

It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson's disease because of 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 copy 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 other was not diagnosed until she was 48.

The reason for the disparity led to an important new discovery by Krainc and his group. The sister who was diagnosed at 16, also had partial loss of Parkin, which, by itself, should not cause Parkinson's.

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

As a result, the scientists realized that Parkin has another important job that had previously been unknown. The gene also functions in a different pathway in the synaptic terminal -- unrelated to its recycling work -- where it controls dopamine release.

With this new understanding of what went wrong for the sister, Northwestern scientists saw a new opportunity to boost Parkin and the potential to prevent the degeneration of dopamine neurons.
"We discovered a new mechanism to activate Parkin in patient neurons," Krainc said. "Now, we need to develop drugs that stimulate this pathway, correct synaptic dysfunction and hopefully prevent neuronal degeneration in Parkinson's."

 

Access the original articles

Press Release:  Northwestern University. "Newly discovered trigger of Parkinson's upends common beliefs." ScienceDaily. ScienceDaily, 15 September 2023. 

Original Trial:   Song, P., Peng, W., Sauve, V., Fakih, R., Xie, Z., Ysselstein, D., Krainc, T., Wong, Y. C., Mencacci, N. E., Savas, J. N., Surmeier, D. J., Gehring, K., & Krainc, D. (2023). Parkinson's disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons. Neuron, S0896-6273(23)00629-3. Advanced online publication. https://doi.org/10.1016/j.neuron.2023.08.018

Disclaimer
This article is compiled from a variety of resources researched and compiled by the contributor. It is in no way presented as an original work.  Every effort has been made to correctly attribute quotes and content. Where possible all information has been independently verified. The Medical Education Network bears no responsibility for any inaccuracies which may occur from the use of third-party sources. If you have any queries regarding this article contact us 

Fact-checking Policy
The Medical Education Network makes every effort to review and fact-check the articles used as source material in our summaries and original material. We have strict guidelines in relation to the publications we use as our source data, favouring peer-reviewed research wherever possible. Every effort is made to ensure that the information contained here is an accurate reflection of the original material. Should you find inaccuracies, out of date content or have any additional issues with our articles, please make use of the contact us form to notify us.