New Role for Alpha-synuclein Uncovered by Researchers
The buildup of alpha-synuclein in cells and brain tissue in Parkinson’s disease patients is linked to the disruption of processes involved in degrading RNA, the template used for protein production, a study has found.
The findings uncover a new biological role for the alpha-synuclein protein, its researchers said.
“Our study offers new insights into a protein that is known to be at the center of the development of Parkinson’s disease and related disorders,” Vikram Khurana, MD, PhD, the study’s corresponding author, chief of the division of movement disorders in the department of neurology at the Brigham and Harvard Medical School, said in a press release.
“This is a protein that is being targeted by current therapeutics, but its function has been elusive. Traditionally, alpha-synuclein has been thought to play a role in binding to the cell membrane and transporting structures known as vesicles. But our study suggests alpha-synuclein is leading a double life,” said Khurana, who is also a principal investigator with the Ann Romney Center for Neurologic Diseases at the Brigham.
The study, “The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability,” was published in Cell.
Alpha-synuclein is a protein abundant in the brains of vertebrate animals. In Parkinson’s, it forms toxic clumps, or aggregates, that disrupt nerve cell activity. Inherited forms of Parkinson’s are sometimes associated with mutations in the SNCA gene responsible for producing alpha-synuclein.
While it’s been believed to play a role in transporting vesicles — small sacs involved in carrying chemicals used for nerve cell communication — the full picture of what alpha-synuclein does in the body is not well understood.
In a series of experiments using yeast, fruit fly, and human cell culture models, the researchers revealed that toxic alpha-synuclein buildup was associated with the disruption of proteins involved in degrading RNA.
Physical interactions were observed between alpha-synuclein and a set of proteins that reside in structures called P-bodies. These proteins, including one called Edc4, are involved in de-capping RNA, a process wherein a protective cap on one end of the RNA molecule is removed, allowing proteins to access and degrade it. These interactions occurred on the same part of alpha-synuclein, called the N-terminus, that seems to be involved in interacting with vesicles, the researchers said.
In nerve cells derived from the stem cells of patients with inherited forms of Parkinson’s, alpha-synuclein similarly appeared to interact directly with Edc4. This interaction was proportionate to alpha-synuclein levels. In other words, as alpha-synuclein accumulated, so did its Edc4 interactions. These increasing associations disrupted other normal P-body processes, leading ultimately to an unusual increase in RNA stability, the researchers said.
Similarly, in Parkinson’s patients’ postmortem brain tissue, it was observed that alpha-synuclein buildup and increasing signs of disease severity were associated with greater disruptions to RNA breakdown.
Further human genetic analyses suggested that the accumulation of mutations in P-body genes may be linked to an increased risk of developing Parkinson’s.
“Despite decades of intense research, [alpha-synuclein] has continued to surprise,” the researchers wrote, noting that the data reveal, “an unexpected aspect of [alpha-synuclein] function and pathology.”
“Our data open up new ways to consider the role of [alpha-synuclein] role in health and disease, in different cellular compartments, and in different cell types,” the researchers wrote, adding that future studies should dive deeper into the role of alpha-synuclein in regulating these RNAs, and how this new knowledge could be targeted for therapeutic intervention.
“If we want to be able to develop treatments that target alpha-synuclein, we need to understand what this protein does and the potential consequences of reducing its level or activity,” Erinc Hallacli, PhD, the study’s lead author and researcher in the department of neurology and the Ann Romney Center for Neurologic Diseases at the Brigham, said.
“This paper provides important information to fill our knowledge gaps about this protein, which may be beneficial for clinical translation,” Hallacli said.