A New Understanding of Parkinson’s Disease Emerges from Sisters’ Tragic Experience

A study from Northwestern Medicine is reshaping conventional wisdom about Parkinson’s disease. Contrary to the prevailing belief that the degradation of dopaminergic neurons initiates the disease, this new study posits that malfunctions in neuronal synapses occur first, prior to any neurodegeneration. This significant insight has implications for the development of new treatments that target synaptic dysfunction before neurons are impacted.

Scientists state that the onset of damage predates the death of dopaminergic neurons.

The Tale of Two Sisters and a Novel Discovery

The research opens fresh possibilities for therapeutic interventions.
Medications should focus on the synapses before neurons begin to deteriorate.

A novel study by Northwestern Medicine is questioning the broadly accepted theory about the cause of Parkinson’s disease.

Previously, it was widely understood that the death of dopaminergic neurons was the initial catalyst for Parkinson’s disease. However, this new study highlights that synaptic dysfunction—the interruption in the small gap that allows impulses to pass between neurons—is the actual precursor to deficits in dopamine and subsequent neurodegeneration.

Parkinson’s affects between 1% and 2% of the general population and manifests as resting tremor, muscular rigidity, and bradykinesia (slowed movements). These motor symptoms result from the gradual decline of dopaminergic neurons in the midbrain.

Reevaluation of Therapeutic Approaches

The study, which was released on September 15 in the scientific journal Neuron, suggests new directions for treatments, according to the researchers.

“Prior to neuronal death, we discovered that dopaminergic synapses are impaired,” said Dr. Dimitri Krainc, chair of neurology at Northwestern University Feinberg School of Medicine and head of the Simpson Querrey Center for Neurogenetics. “These findings lead us to propose that intervening at the synaptic level could offer a more effective therapeutic strategy.”

This research employed neurons derived from human patients, an important methodological choice given that dopamine neurons in mice and humans have different physiological characteristics and thus, findings in mice are not applicable to humans. This was underscored in recent research by Dr. Krainc published in the journal Science.

Synaptic Dysfunction in Genetic Forms of Parkinson’s

The Northwestern team discovered that in various genetic variations of Parkinson’s disease, dopaminergic synapses are not functioning properly. This research, along with other recent work by Dr. Krainc’s lab, begins to fill a significant knowledge gap in how different genes connected to Parkinson’s lead to the degeneration of human dopaminergic neurons.

Deciphering Neuronal Waste Management

Picture two individuals responsible for managing the recycling of mitochondria, the cellular energy factories, in a neuronal recycling plant. If dysfunctional mitochondria are not properly recycled or eliminated— a process known as mitophagy—cellular dysfunction can ensue. Two key genes involved in this process are PINK1 and Parkin.

It is known that individuals with mutations in both copies of either PINK1 or Parkin genes develop Parkinson’s due to flawed mitophagy.

An Unfortunate Genetic Circumstance Leads to a Discovery

Two sisters were born lacking the PINK1 gene since both their parents were missing a copy. This made them highly susceptible to Parkinson’s. However, one sister was diagnosed at 16, while the other received her diagnosis at 48. This discrepancy led researchers to a groundbreaking new understanding.

The sister diagnosed at 16 also had a partial deficiency of the Parkin gene, which alone shouldn’t trigger Parkinson’s. This led the scientists to conclude that Parkin also plays a role in another synaptic function that controls dopamine release. Understanding this previously unknown function of Parkin has provided new avenues for drug development targeting dopamine neuron preservation.

“We have identified a new way to activate Parkin in patient neurons,” stated Dr. Krainc. “Our next step is to develop drugs that will stimulate this newly discovered pathway, correct the synaptic dysfunction, and potentially halt neuronal degeneration in Parkinson’s disease.”

References and Acknowledgements

The lead author of the study is research assistant professor Pingping Song, who is part of Dr. Krainc’s laboratory. Other contributors include Wesley Peng, Zhong Xie, Daniel Ysselstein, Talia Krainc, Yvette Wong, Niccolò Mencacci, Jeffrey Savas, and D. James Surmeier from Northwestern, as well as Kalle Gehring from McGill University.

The research was funded by grants from the National Institutes of Health, specifically from the National Institute of Neurological Disorders and Stroke.

Frequently Asked Questions (FAQs) about Parkinson’s Disease Research

More about Parkinson’s Disease Research

• Northwestern Medicine Official Website
• Journal Neuron
• National Institute of Neurological Disorders and Stroke
• Dr. Dimitri Krainc’s Professional Profile
• Overview of Parkinson’s Disease
• Mitophagy and Neurodegenerative Diseases
• National Institutes of Health (NIH)
• Understanding Dopaminergic Neurons
• Synaptic Dysfunction in Neurodegenerative Diseases