More than 300 Genes Impact Toxicity of Protein Linked to Brain Function, Study Finds

Researchers have identified more than 300 genes that influence alpha-synuclein’s toxicity, and among them are many known to predispose individuals to Parkinson’s disease (PD), researchers said. The finding provides new insight into what mechanisms lead to the disease.

The hallmark of Parkinson’s disease is the formation of alpha-synuclein protein aggregates, which are toxic to neurons and promote the loss of brain function, but the disease may also be caused by several gene mutations.

Two studies in the journal Cell Systems have tackled that issue.

In “Genome-Scale Networks Link Neurodegenerative Disease Genes To Alpha-Synuclein Through Specific Molecular Pathways,” researchers used yeast to identify genes associated with alpha-synuclein’s toxic effect — some of which can be found in humans.

“In the first paper, we used powerful and unbiased genetic tools in the simple Baker’s yeast cell to identify 332 genes that impact the toxicity of alpha-synuclein,” Vikram Khurana, the studies’ first author, said in a news release. “Among them were multiple genes known to predispose individuals to Parkinson’s — so we show that various genetic forms of Parkinson’s are directly related to alpha-synuclein. Moreover, the results showed that many effects of alpha-synuclein have been conserved across a billion years of evolution from yeast to human.”

In the second study,  “In Situ Peroxidase Labeling and Mass-Spectrometry Connect Alpha Synuclein Directly To Endocytic Trafficking And mRNA Metabolism In Neurons,” researchers used neurons to track proteins in the vicinity of alpha-synuclein that may interact with it.

“(F)or the first time, we were able to visualize the protein’s location, at minute scale, under physiologic conditions in an intact brain cell,” said Chee Yeun Chung, senior author of the studies.

Together, the works showed that alpha-synuclein interfered with the rate of protein production in the cell, as well as the transport of proteins between cellular compartments.

“These interactions can explain connections between different Parkinson’s genetic risk factors,” the researchers wrote.

The team had to develop computational tools to find patterns of protein interaction in both yeast and humans, and to make predictions about which human genes could be associated with alpha-synuclein’s toxicity.

“We now have a system to look at how seemingly unrelated genes come together to cause Parkinson’s and how they are related to the protein that misfolds in this disease,” Khurana said.

Researchers confirmed their results using generated neurons from Parkinson’s patients with different mutations. The protein interactions they had predicted allowed them to identify abnormal mechanisms shared among the patients.

“We believe these methods could pave the way for developing patient-specific treatments in the future,” Khurana said.