A New Study Challenges Common Beliefs About Parkinson’s Disease
Introduction
Parkinson’s disease is a neurodegenerative disorder that affects a significant portion of the population. For years, it has been widely believed that the degeneration of dopaminergic neurons is the primary trigger for Parkinson’s disease. However, a new study from Northwestern Medicine challenges this common belief, suggesting that a dysfunction in neuron synapses precedes neurodegeneration and leads to dopamine deficits.
The Study’s Findings
The study conducted by Northwestern Medicine focused on investigating patient-derived midbrain neurons, as it is critical to understand the physiology of human dopamine neurons, which differs from that of mouse neurons. The researchers discovered that dopaminergic synapses do not function properly in various genetic forms of Parkinson’s disease. This finding, along with other recent studies, addresses one of the major gaps in the field: understanding how different Parkinson’s-related genes contribute to the degeneration of human dopaminergic neurons.
Reconsidering Parkinson’s Disease Development
Traditionally, it has been believed that the loss of dopaminergic neurons is the initial event in the development of Parkinson’s disease. The new study challenges this notion by suggesting that dysfunction in neuron synapses precedes neurodegeneration. This finding opens up a new avenue for developing therapies aimed at targeting dysfunctional synapses before the degeneration of neurons occurs.
The Role of Dopamine
Parkinson’s disease is characterized by motor symptoms such as resting tremor, rigidity, and slowness of movement. These symptoms are a result of the progressive loss of dopaminergic neurons in the midbrain. Dopamine is a neurotransmitter that plays a crucial role in regulating movement and emotional responses. A deficit of dopamine in the brain leads to the motor symptoms associated with Parkinson’s disease.
Understanding Mitochondrial Dysfunction
The study also sheds light on the role of mitochondrial dysfunction in Parkinson’s disease. Mitochondria are the cell’s energy producers, and dysfunctional mitochondria can cause cellular dysfunction. The process of recycling or eliminating old mitochondria is called mitophagy, which is crucial for maintaining cellular health. Dysfunction in the genes responsible for mitophagy, namely Parkin and PINK1, has been linked to Parkinson’s disease.
The Story of Two Sisters
The study further explores the effect of Parkin mutations on Parkinson’s disease development by examining the case of two sisters born without the PINK1 gene. Both sisters were at high risk for Parkinson’s disease, but one sister was diagnosed at the age of 16 while the other was not diagnosed until age 48. The difference in onset led researchers to discover that Parkin has another important task unrelated to mitophagy. The gene also plays a role in controlling the release of dopamine in the synaptic terminal, providing a potential target for therapeutic intervention.
The Future of Parkinson’s Disease Therapies
The findings of this study offer new hope for the development of Parkinson’s disease therapies. By targeting dysfunctional synapses and boosting the activity of the Parkin gene, researchers believe that it may be possible to prevent the degeneration of dopamine neurons. This discovery opens up a new pathway for treatment strategies that could potentially slow down or halt the progression of the disease.
Conclusion
In conclusion, a new study from Northwestern Medicine challenges the common belief that the degeneration of dopaminergic neurons is the primary trigger for Parkinson’s disease. The study suggests that dysfunction in neuron synapses precedes neurodegeneration and leads to dopamine deficits. This discovery provides new opportunities for developing therapeutic interventions that target dysfunctional synapses and boost the activity of genes such as Parkin. By understanding the complex mechanisms underlying Parkinson’s disease development, researchers hope to improve the quality of life for individuals affected by this debilitating condition.
Summary:
Degeneration of dopaminergic neurons has long been believed to be the first event in Parkinson’s disease. However, a new study challenges this belief, suggesting that dysfunction in neuron synapses precedes neurodegeneration and leads to dopamine deficits. The study investigated patient-derived midbrain neurons and found that dopaminergic synapses do not function properly in various genetic forms of the disease. This discovery opens up new possibilities for therapeutic interventions that target dysfunctional synapses and boost the activity of genes like Parkin. By better understanding the mechanisms underlying Parkinson’s disease, researchers hope to develop more effective treatments.
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A new study from Northwestern Medicine challenges common beliefs about what triggers Parkinson’s disease.
Degeneration of dopaminergic neurons is widely accepted as the first event leading to Parkinson’s. But the new study suggests that a dysfunction in neuron synapses (the small gap through which one neuron can send an impulse to another neuron) leads to dopamine deficits and precedes 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 on September 15 in NeuronThey open a new avenue for therapies, the scientists said.
“We show that dopaminergic synapses become dysfunctional before neuronal death occurs,” said senior 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 neurons degenerate may represent a better therapeutic strategy.”
The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have different physiology and the findings in mouse neurons are not translatable to humans, as highlighted in the research by Krainc recently published in Science.
Northwestern scientists discovered that dopaminergic synapses do not function properly in various genetic forms of Parkinson’s disease. This work, along with other recent studies from Krainc’s lab, addresses one of the major gaps in the field: how different Parkinson’s-related genes lead to the degeneration of human dopaminergic neurons.
Neuronal recycling plant
Let’s imagine two workers in a neural recycling plant. Its job is to recycle mitochondria, the cell’s energy producers, that are too old or overworked. If dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or eliminating 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 old mitochondria onto the path to be recycled or eliminated.
It is well established that people who carry mutations in both copies of PINK1 or Parkin develop Parkinson’s disease due to ineffective mitophagy.
The story of two sisters whose illness helped advance Parkinson’s research
Two sisters were unfortunate enough to be born without the PINK1 gene, because each of their parents was missing one copy of the critical gene. This put the sisters at high risk for Parkinson’s disease, but one sister was diagnosed with the disease at age 16, while the other was not diagnosed until age 48.
The reason for the disparity led to an important new discovery by Krainc and his group. The sister who was diagnosed at age 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, scientists realized that Parkin has another important task that was previously unknown. The gene also functions in a different pathway in the synaptic terminal, unrelated to its recycling job, where it controls the release of dopamine. 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 degeneration of dopamine neurons.
“We discovered a new mechanism to activate Parkin in patients’ neurons,” Krainc said. “We now need to develop drugs that stimulate this pathway, correct synaptic dysfunction, and hopefully prevent neuronal degeneration in Parkinson’s.”
The study’s first author is Pingping Song, a research assistant professor in Krainc’s lab. Other authors include Wesley Peng, Zhong Xie, Daniel Ysselstein, Talia Krainc, Yvette Wong, Niccolò Mencacci, Jeffrey Savas and D. James Surmeier of Northwestern and Kalle Gehring of McGill University.
The title of the paper is “Parkinson’s disease-related parkin mutation impairs synaptic vesicle recycling in human dopaminergic neurons.”
This work was supported by National Institutes of Health grants R01NS076054, R3710 NS096241, R35 NS122257, and NS121174, all from the National Institute of Neurological Disorders and Stroke.
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