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Study challenges widely accepted theory on origin of Parkinson's disease

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Illinois | September 17, 2023 11:15:09 PM IST
A recent study from Northwestern Medicine challenges a widely accepted theory on the origins of Parkinson's disease.

Dopaminergic neurodegeneration is generally recognized to be the primary trigger of Parkinson's disease. The latest study, however, contends that dopamine deficits and neurodegeneration are caused by malfunctions in the synapses, which are the microscopic gaps between neurons via which they may communicate.

Parkinson's disease, which affects 1 percent to 2 percent of the population, is distinguished by bradykinesia (slowness of movement), rigidity, and resting tremor. These motor symptoms are brought on by the gradual loss of dopaminergic midbrain neurons.

The findings, which will be published in Neuron, open up a new avenue for therapies, according to the researchers.

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 Parkinsons disease. This work, together with other recent studies by Kraincs lab, addresses one of the major gaps in the field: how different genes linked to Parkinsons lead to degeneration of human dopaminergic-neurons.

Imagine two workers in a neuronal recycling plant. Its 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 Parkinsons 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 Parkinsons 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 Parkinsons.

There must be a complete loss of Parkin to cause Parkinsons 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 Parkinsons. (ANI)

 
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