New research contradicts a commonly held belief about Parkinson’s disease.

The Real First Sign of Parkinson’s? It’s Not in the Neuron But the Gap Between, Says New Study

The decline of dopaminergic neurons has long been considered the primary precursor to Parkinson’s. However, recent research indicates that the real issue may originate in the synapses of the neuron – the minuscule space where one neuron communicates with another – resulting in dopamine shortages even before the neuron starts to degenerate.

Parkinson’s, a condition experienced by 1-2% of the global populace, manifests as tremors at rest, muscular rigidity, and bradykinesia (movement delay). These symptoms stem from the dwindling numbers of dopaminergic neurons in the midbrain.

The findings of the study were published today in the journal Neuron.

Dr. Dimitri Krainc, lead author of the research and also the chair of neurology at Northwestern University Feinberg School of Medicine, commented, “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.”

Notably, the research focused on neurons derived from human midbrain samples. This emphasis is pivotal since mouse and human dopamine neurons diverge in their physiological attributes. Consequently, inferences drawn from mouse models don’t always align with human biology, a point underlined in Krainc’s prior work featured in Science.

The Northwestern research team identified malfunctions in dopamine-related synapses across diverse genetic manifestations of Parkinson’s disease. Krainc’s ongoing investigations elucidate the mechanisms by which varying genes associated with Parkinson’s expedite the breakdown of human dopamine-producing neurons.

Neural Waste Management Facility

Visualize a duo working tirelessly in a facility designed for neural waste management. Their core responsibility? Ensuring the timely recycling of mitochondria, the cell’s power generators, especially when they age or become inefficient. When these worn-out mitochondria aren’t dealt with, they risk disrupting the cell’s proper functioning. This rejuvenation and removal of aging mitochondria is known as mitophagy. Orchestrating this intricate process are two key genes, Parkin and PINK1. Typically, PINK1 triggers Parkin to shepherd these older mitochondria towards the appropriate recycling or elimination routes.

Research indicates that individuals with mutations in both versions of the PINK1 or Parkin genes often succumb to Parkinson’s disease, primarily due to this recycling process, mitophagy, not functioning optimally.

The Tale of Siblings and Their Contribution to Parkinson’s Insights

Born into an unexpected genetic predicament, two siblings lacked the PINK1 gene, due to each of their parents missing one crucial gene variant. This genetic landscape poised them towards a heightened risk of Parkinson’s disease. However, their health trajectories were notably different: one sister faced a diagnosis at a mere 16 years, while the other remained undiagnosed until she reached 48.

This striking age difference in diagnosis intrigued Krainc and his team of researchers. Diving deeper, they found that the younger sister, aside from lacking PINK1, also had an incomplete Parkin gene.

Though a mere partial absence of Parkin shouldn’t prompt Parkinson’s, it raised the question, “Why did the sister with only a partial loss of Parkin get the disease more than 30 years earlier?” as pondered by Krainc.

In unraveling this mystery, the research team uncovered an untapped function of the Parkin gene. Beyond its established recycling role, Parkin was identified as a key player in a distinct synaptic pathway, particularly influencing dopamine release. With this revelation about the younger sister’s genetic makeup, the researchers at Northwestern identified a promising new way to enhance Parkin functionality, potentially thwarting dopamine neuron degeneration.

Krainc emphasized, “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.”

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