A potential breakthrough in the understanding of Parkinson's disease might come from the genetic puzzle of two sisters.

A long-held theory on the cause of Parkinson's disease has been refuted by researchers in a ground-breaking finding that was published in the journal Neuron, providing new insight into this crippling neurological ailment. According to their findings, Parkinson's disease may be triggered by synapses, which are microscopic gaps that permit neurons to communicate with one another. This discovery provides encouraging new directions for possible treatments that may have a major influence on the lives of those who are afflicted with the illness.

A common neurological condition, Parkinson's disease affects 1% to 2% of people worldwide. Many motor symptoms, such as stiffness, slowness of movement, and resting tremors, are what define it. The progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), a particular region of the brain, is the cause of these symptoms.

The cause of Parkinson's disease has long been a challenging riddle for scientists to crack. Although the exact cause is yet unknown, aging, environmental factors, and genetics all seem to be involved. It is well recognized that dopaminergic neurons, which generate the essential neurotransmitter dopamine, play a key role in the illness.

It was long believed that the first step in the development of Parkinson's disease was the death of dopaminergic neurons. This new research, however, casts doubt on that notion by implying that the malfunction in the connections of these neurons may occur before their degeneration.

An unusual example involving two sisters who were genetically predisposed to Parkinson's disease because of a mutation in the PINK1 gene spurred interest in this particular line of inquiry. The diagnosis was made for one sister when she was sixteen and for the other when she was forty-eight years old.

Leading the study was Dimitri Krainc, the director of the Simpson Querrey Center for Neurogenetics and chair of neurology at Northwestern University Feinberg School of Medicine. "We encountered two sisters with Parkinson's that had disease onset 30 years apart and we tried to explain this discrepancy by studying their genes."

They found that in addition to having the PINK1 mutation, the sibling, who was identified at age 16, also had a partial deletion of the parkin gene. The scientists began to wonder if Parkin played a previously unidentified part in the illness after learning this information.

"Parkin's disease cannot be caused by anything other than the total absence of parkin. What then caused the sister who had only a partial lack of parkin to get the illness over thirty years earlier? stated Krainc.

The process of "recycling" aged or overworked mitochondria involves both parkin and PINK1. If left untreated, dysfunctional mitochondria can lead to cellular problems. Mitophagy is the term for this process of recycling aged mitochondria. Parkinson's disease can arise in individuals who have mutations in both copies of the parkin or PINK1 gene, which results in impaired mitophagy.

The study was conducted using patient-derived midbrain neurons, which is important because the physiological properties of mouse and human dopamine neurons differ, meaning that results from rodent models cannot be directly applied to humans.

The scientists' investigation revealed a critical function for parkin that was previously unidentified. Apart from its recycling role, parkin functions in a distinct pathway inside the synaptic terminal. This route controls the release of dopamine and is unrelated to mitophagy.

For the general public, the most important thing to remember is that neuronal death is not always the first sign of Parkinson's disease. Rather, it originates from the dysfunction of synapses, which are the hubs of communication where neurons share important information. According to Krainc, the results suggest that synapse dysfunction occurs much before neuronal degeneration in Parkinson's disease.

This finding is noteworthy because it suggests that focusing on the damaged synapses may be a fresh approach to treating Parkinson's disease. We may have a better chance of controlling or perhaps avoiding the crippling effects of Parkinson's if we act before neuron loss takes place.

Krainc stressed that although the research brings greater optimism, there are still issues and questions that need to be resolved. "We need to find a way to target such synaptic dysfunction therapeutically as early as possible," the speaker issued a warning. Stated differently, the path toward a useful treatment grounded in this finding remains unfinished, and additional research is required to identify efficacious approaches.

Still, there are significant ramifications for this discovery. It emphasizes how crucial it is to comprehend each patient's unique genetic basis for Parkinson's disease. "It is important to examine each patient's genes because understanding the genetic basis of the disease helps with therapeutic strategies," Krainc recommended.

The researchers, Pingping Song, Wesley Peng, Veronique Sauve, Rayan Fakih, Zhong Xie, Daniel Ysselstein, Talia Krainc, Yvette C. Wong, Niccolò E. Mencacci, Jeffrey N. Savas, D. James Surmeier, Kalle Gehring, and Dimitri Krainc, wrote the paper "Parkinson's disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons."

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