Researchers Identify Gene Networks Underlying Parkinson’s Development

Researchers have found new gene networks associated with the development of Parkinson’s disease, which may help them understand the underlying mechanisms of this neurodegenerative disorder and identify potential new therapeutic targets.

The study, “The landscape of multiscale transcriptomic networks and key regulators in Parkinson’s disease,” was published in the journal Nature Communications.

Parkinson’s disease is a neurodegenerative disorder characterized by the impairment or loss of nerve cells (neurons) responsible for producing dopamine — a chemical messenger that transmits nerve signals from one neuron to another and plays a role in many basic functions of the brain, such as movement control, reward, and memory.

The substantia nigra, a brain region that controls balance and movement, is the most affected brain area during Parkinson’s progression, with the greatest extent of nerve cell death.

Some cases of Parkinson’s are directly caused by genetic mutations (more than 20 mutations have been reported), but these cases are rare. In most cases, about 80%, the origin of the disease is unknown. However, Parkinson’s is suspected to result from a complex interplay between multiple genes and environmental factors.

In the study, researchers at the Icahn School of Medicine at Mount Sinai sought to investigate the complex network of genes involved in Parkinson’s and how they interact with each other to drive the disease.

“This study offers a novel approach to understanding the majority of cases of Parkinson’s,” Bin Zhang, PhD, a professor and director at the Icahn School of Medicine, and one of the senior authors of the study, said in a press release.

“The strategy not only reveals new drivers, but it also elucidates the functional context of the known Parkinson’s disease risk factor genes,” Zhang added.

The development of high-throughput molecular profiling techniques has advanced the research of complex diseases. It has helped scientists uncover patterns of gene activity and regulation, and find links between them that point to novel pathways and genetic targets for certain diseases.

Supported by the National Institutes of Health and the Accelerating Medicines Partnership – Alzheimer’s Disease program, Zhang and his team developed a method to analyze large datasets collected from patient samples, called multiscale gene network analysis (MGNA), which they had applied to understand complex diseases, ranging from Alzheimer’s to cancer.

The team used MGNA to analyze a combined data set of eight studies that included postmortem samples of the substantia nigra of 83 Parkinson’s patients.

By comparing this data with that of 70 controls who did not have Parkinson’s, the scientists identified a number of key genetic regulators that had not been associated with the disease before.

One of the genes — called STMN2 — stood out as a key regulator of the Parkinson’s molecular network. The gene is normally active in neurons that produce dopamine, providing instructions for making a protein called stathmin 2. The analysis revealed that STMN2 was down-regulated in the brains of people with Parkinson’s.

To directly test the effects of STMN2 on Parkinson’s disease, the team genetically engineered mice to dampen the activity of STMN2 in the substantia nigra as a way to mimic what happens in the brain of human patients.

This manipulation “turned on” nine genes known to increase the risk of Parkinson’s disease, and mice developed Parkinson’s-like symptoms such as a loss of dopaminergic neurons in the substantia nigra and an increase in toxic clumps of alpha-synuclein protein, two hallmarks of the disease.

The animals also had trouble in motor tasks such as maintaining balance — suggesting that they were impaired in their ability to control movements, which resembled Parkinson’s motor symptoms.

Although the findings need to be validated in larger studies, “The work opens up a new avenue for studying the disease,” said Zhenyu Yue, PhD, a professor and director at the Icahn School of Medicine and one of the senior leaders of the research.

“The new genes we identified suggest that new pathways should be considered as potential targets for drug development, particularly for idiopathic [of unknown cause] Parkinson’s cases,” he added.