A recent study is challenging long held beliefs about Parkinson’s disease, and the findings could lead to new and improved avenues of treatment.
The widely accepted explanation for what causes the disease is the degeneration of dopaminergic neurons, the main source of dopamine in the central nervous system. Found in the midbrain, they contribute to multiple brain functions, including voluntary movement and behavioral processes like mood, addiction, reward, and stress. Damage to these neurons results in motor issues like resting tremors, rigidity, and slowness of movement that are common in Parkinson’s patients.
But researchers out of Northwestern University Feinberg School of Medicine found that something else precedes the neurons’ degeneration in various genetic forms of the disease: a dysfunction within the neurons’ synapses, the junctions that allow signals to pass from one cell to another. Identifying this dysfunction opens up the possibility of new drugs that would specifically target the synapses before degeneration occurs, and thus before Parkinson’s symptoms begin.
“We showed that dopaminergic synapses become dysfunctional before neuronal death occurs,” lead author Dr. Dimitri Krainc, chair of neurology at Northwestern University, said in a news release from the institution. “Based on these findings, we hypothesize that targeting dysfunctional synapses before the neurons are degenerated may represent a better therapeutic strategy.”
Over 10 million people are living with Parkinson’s worldwide. Though the disease isn’t always hereditary, two genes are thought to be associated with dopaminergic neuron degeneration: PINK1 and Parkin. These genes can be thought of as “two workers in a neuronal recycling plant,” per the Northwest University news release. The genes are responsible for removing old or overworked mitochondria; mitochondria generate energy, which is why they’re often referred to as the “powerhouses of the cell.”
People who are born with mutations in both copies of either PINK1 or Parkin have a higher risk of developing Parkinson’s disease because the genes’ ability to work together is compromised. This can lead to a “toxic buildup” of dopamine in the cells, per Science Alert, which can lead to the degeneration, something dopaminergic neurons are particularly susceptible to.
To reach their inevitable discovery, the team looked at the case of two sisters. Both were born without the PINK1 gene, and one also had partial loss of function of the Parkin gene. The latter was diagnosed with Parkinson’s at just 16 years old, while the other was diagnosed at 48. That gap presented an area of exploration for the scientists.
“There must be a complete loss of Parkin to cause Parkinson’s disease,” explained Krainc. “So, why did the sister with only a partial loss of Parkin get the disease more than 30 years earlier?”
He and his colleagues realized that Parkin has a previously unknown role to play in controlling the release of dopamine through the synapses, something unrelated to its job at the aforementioned mitochondrial recycling plant. Even a partial loss of the Parkin’s gene could result in dysfunction within the synapse and would explain the sister’s early diagnosis.
“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.”
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