Parkinson's gene may impair how new neurons are made

A gene defect linked to Parkinson’s disease not only causes the early death of neurons, but may also impair the process that generates neurons in the brain throughout a person’s lifetime.

That’s according to a new international study, led by The University of Sheffield’s Neuroscience Institute and published in the journal Scientific Reports. The study used two model systems to measure how inactivation of the PINK1 gene affects dopamine-producing neurons in the adult brain, and may have a significant impact on the future treatment of Parkinson’s patients.

Dopamine-producing neurons are the most severely affected brain cells in Parkinson’s disease, which is the second most common neurodegenerative disease. It is typically thought that Parkinson’s genes, such as PINK1, cause early death of these neurons, with symptoms developing when neuron numbers fall. However, the researchers found that a deficiency in PINK1 resulted in fewer dopamine-producing neurons being made throughout a lifetime.

“Neurogenesis is the process by which new neurons are formed in the brain,” explained Professor Oliver Bandmann, from the Sheffield Institute for Translational Neuroscience (SITraN). “Recent evidence suggests that this process is ongoing throughout life but the relevance of this is poorly understood in neurodegenerative disorders such as Parkinson’s disease.

“We know that mutations in the PINK1 gene cause an early-onset, inherited form of Parkinson’s disease. If we can further our understanding about the impact of this genetic mutation on the dopamine-producing neurons, we can develop new therapeutic approaches that aim to mitigate those effects.”

In collaboration with the University of Luxembourg, the researchers used two complementary model systems to examine how neurons are reproduced throughout our lifetime. As explained by Sheffield’s Professor Marysia Placzek, “We used the zebrafish to demonstrate that dopamine-producing neurons are generated into adulthood at a rate that decreases with age and that PINK1 deficiency impairs neurogenesis of these neurons, significantly in early adult life. Our international collaborators then confirmed these results in a human organoid cell model.”

The observation of impaired adult dopaminergic neurogenesis in PINK1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in Parkinson’s disease. The development of novel treatments and therapies to slow down disease progression, halt or reverse Parkinson’s may now focus on enhancing the generation of new dopamine-producing neurons, rather than just trying to protect these neurons from dying later.

Future research will aim to identify the precise mechanisms that link Parkinson’s genes to neurogenesis. This will allow us to explore the development of gene therapy or small molecule approaches to enhance neurogenesis in the brain of patients with Parkinson’s.

Image caption: Old and newly made dopamine-producing nerve cells in the zebrafish brain.

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