Incredible research upends what scientists know about Parkinson’s disease
Parkinson’s belief centers around the degradation of dopaminergic neurons as the initial trigger for this neurodegenerative condition.
[Sept. 16, 2023: Staff Writer, The Brighter Side of News]
Parkinson's disease has perplexed the scientific community for years. (CREDIT: Creative Commons)
Parkinson's disease has perplexed the scientific community for years. The age-old belief centers around the degradation of dopaminergic neurons as the initial trigger for this neurodegenerative condition. However, a surprising study is now refuting this theory.
Drawing the world's attention to an often-overlooked cellular component – the neuron's synapses, the study contends that it's the dysfunction within these tiny gaps – responsible for transmitting impulses between neurons – that causes dopamine deficits and precedes neuron degradation.
To understand the magnitude of this revelation, it's essential to grasp the scale of Parkinson's impact. With 1-2% of the global population grappling with this disease, countless individuals endure symptoms such as resting tremors, rigidity, and bradykinesia – a heart-wrenching slowness of movement. These symptoms stem from the ongoing loss of dopaminergic neurons within the midbrain.
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The groundbreaking findings are slated for a September 15th unveiling in the esteemed scientific journal, Neuron. Dr. Dimitri Krainc, the leading light behind this research, vocalizes the profound implications of their discoveries: “We showed that dopaminergic synapses become dysfunctional before neuronal death occurs. Based on these findings, we hypothesize that targeting dysfunctional synapses before the neurons are degenerated may represent a better therapeutic strategy.”
Dr. Krainc's emphasis on examining patient-derived midbrain neurons is pivotal. His recent paper in Science illustrates a crucial point: findings derived from mouse neurons aren't translatable to humans due to inherent physiological differences. Hence, human dopamine neurons offer a more accurate lens to view and comprehend this disease.
Zooming in on Parkinson's genetic forms, the Northwestern research team discerned that dopaminergic synapses malfunctioned. This discovery, in tandem with Dr. Krainc's recent endeavors, addresses a significant gap in understanding how various Parkinson’s-linked genes lead to the degeneration of human dopaminergic neurons.
Journey Inside the Neuronal Recycling Plant
To simplify, envision two diligent workers at a neuronal recycling facility. Their mission? To recycle or dispose of aged, overworked mitochondria – the cell's powerhouse. If these dysfunctional mitochondria linger, cellular havoc ensues. The recycling process, termed mitophagy, is orchestrated by the genes Parkin and PINK1. In ideal conditions, PINK1 activates Parkin, ensuring old mitochondria are set on their recycling journey.
The established consensus in the scientific realm is that individuals bearing mutations in either the PINK1 or Parkin genes, in both gene copies, are prone to Parkinson’s due to disrupted mitophagy.
A Tale of Two Sisters and a Leap in Parkinson’s Research
An intriguing case of two siblings serves as a testament to the complexity of this disease. Both were bereft of the PINK1 gene, courtesy of their parents’ genetic makeup, predisposing them to Parkinson's. Yet, their disease trajectories diverged dramatically. One sister received a Parkinson's diagnosis at a mere 16, while the other remained unaffected until 48.
Dopamine-mediated modification of GCase and lysosomal dysfunction in PD patient neurons. (CREDIT: Science)
Unearthing the reason for this stark difference, Dr. Krainc's team had an epiphany. While the earlier-diagnosed sister had a partial loss of Parkin, this alone shouldn’t precipitate Parkinson’s. Dr. Krainc pondered, “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?”
The puzzle's missing piece? The discovery that the Parkin gene also governs dopamine release at the synaptic terminal, separate from its recycling duties. This revelation underscored Parkin's dual functionality, paving the way for innovative therapeutic strategies to bolster Parkin, potentially staving off dopamine neuron degeneration.
Mitochondrial antioxidants and calcium modulators attenuate the toxic cascade in DJ-1 mutant dopaminergic neurons. (CREDIT: Science)
The future seems hopeful as Dr. Krainc optimistically shares, “We discovered a new mechanism to activate Parkin in patient neurons. Now, we need to develop drugs that stimulate this pathway, correct synaptic dysfunction, and hopefully prevent neuronal degeneration in Parkinson’s.”
This transformative study owes its success to a team of dedicated researchers, including first author Pingping Song from Krainc’s lab, and contributors like Wesley Peng, Zhong Xie, Daniel Ysselstein, Talia Krainc, Yvette Wong, Niccolò Mencacci, Jeffrey Savas, and D. James Surmeier from Northwestern. Not forgetting Kalle Gehring from McGill University, their collective efforts are setting the stage for a brighter future in Parkinson's research and treatment.
Keywords: Parkinson’s disease, Northwestern Medicine, dopaminergic neurons, synapses, dopamine, neuron, Neuron journal, Dr. Dimitri Krainc, genetic forms, mitochondrial recycling, mitophagy, PINK1, Parkin, synaptic terminal.
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