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Close up of a senior male with Parkinson's disease.
Parkinson’s disease is characterized by resting tremors, rigidity, and bradykinesia, which arise due to the progressive loss of dopaminergic neurons in the midbrain.
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New Roles of Genes Driving Parkinson’s Onset Discovered

Scientists report that damage starts much earlier than the death of dopamine neurons

Northwestern University
Published:Sep 15, 2023
|2 min read
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CHICAGO — 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 leads to deficits in dopamine and precedes neurodegeneration.

Parkinson’s disease affects 1–2 percent of the population and is characterized by resting tremors, rigidity, and bradykinesia (slowness of movement). These motor symptoms are due to the progressive loss of dopaminergic neurons in the midbrain.

The findings open a new avenue for therapies per the scientists. “We showed that dopaminergic synapses become dysfunctional before neuronal death occurs,” said lead author Dr. Dimitri Krainc, MD, PhD, 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 differ in physiology: Findings in the mouse neurons may not be translatable to humans, as highlighted in Krainc's recent research.

Northwestern scientists found that dopaminergic synapses didn’t function 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 the degeneration of human dopaminergic neurons. 

Neuronal recycling plant

Imagine two workers in a neuronal recycling plant; their job is to recycle old and stressed mitochondria. 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 (PARK2) and PINK1 (PARK6). 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. 

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.

The undiscovered role of Parkin

As a result, the scientists realized that Parkin had another critical role that was previously unknown. The gene also functions in a different pathway in the synaptic terminal, 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,” said Krainc. “Now, we need to develop drugs that stimulate this pathway, correct synaptic dysfunction, and hopefully prevent neuronal degeneration in Parkinson’s.”

- This press release was originally published on the Northwestern University website