The Surprising Double Life of a Parkinson’s-Related Protein

The Context: The major hallmark of Parkinson’s disease is an accumulation of a protein in the brain called alpha-synuclein. While alpha-synuclein has been the focal point of Parkinson’s research for decades, scientists still know little about its role in the brain and how it contributes to the disease.

The Study: Scientists have identified an entirely new role alpha-synuclein plays in our cells: it binds to structures called P-bodies to regulate how our genes are expressed via mRNA (a cell’s messenger molecules). The study, published in Cell by NYSCF – Robertson Stem Cell Investigator Vikram Khurana, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School, suggests alpha-synuclein has wider ranging impacts on our cells than previously thought. The team also found that people with mutations in genes related to P-bodies have a higher risk of developing Parkinson’s.

The Importance: This study elucidates a surprising new and fundamental role of alpha-synuclein in cellular biology, opening new opportunities for therapeutically targeting a major culprit of Parkinson’s disease.

“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,” said Dr. Khurana, chief of the Division of Movement Disorders within the Department of Neurology at the Brigham and Harvard Medical School, in an article by Brigham and Women’s. 

“If a protein is targeted by therapy, it is important to know its function in order to determine the potential consequences of reducing its level or activity,” he added in an interview with The American Parkinson’s Disease Association. “This paper provides important information to fill our knowledge gap here.”

“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.”

A New Regulator of mRNA

The team first learned from experiments in yeast, fruit flies, and human cells that alpha-synuclein was doing more than binding to vesicles (little sacs that transport materials within a cell): it was binding to cellular structures called ‘P-bodies’ that regulate gene expression by directing behavior of mRNA (messenger molecules created by DNA that tell a cell what proteins to make).

The scientists then decided to take a closer look at P-bodies in the cells of people with Parkinson’s. They generated stem cells from patients with the disease and found that P-bodies weren’t functioning the way they should, in turn causing abnormal gene regulation.

They then looked at brain tissue collected postmortem from Parkinson’s patients and found the same thing: dysfunctional P-bodies. 

“In neurons derived from Parkinson’s patient stem cells and in the human brain, when alpha-synuclein abnormally accumulates, the physiologic structure and function of the P-body is lost,” said Dr. Khurana.

A deeper dive into the genetics of Parkinson’s-affected cells confirmed what the scientists suspected: patients who accumulate mutations in P-body genes appear more likely to develop the disease.

The Road to Treatments

“The discoveries in this paper open up new potential targets for therapies that prevent or slow down the progression of Parkinson’s and related synucleinopathies,” said Dr. Khurana.

In order to get there, there are still a few outstanding questions that Dr. Khurana plans to tackle.

“First, we need to better understand how the P-body machinery interacts with alpha-synuclein,” he noted. “Second, more clarity is needed on which of the P-body machinery components might be the best targets for a therapeutic intervention. Third, more detailed genetic studies are required to understand how much mutations in P-body genes contribute to risk of Parkinson’s and disease progression.”

Dr. Khurana hopes this work will also help scientists better classify patients and tailor treatments to their specific form of Parkinson’s.

“Parkinson’s may arise in different ways in different patients, and a “one size fits all” strategy may not work for the disease,” he remarked. “The findings in this paper might help us “stratify” or “bin” patients into different categories and, in time, develop more targeted therapies for patients.”

As a clinician and a researcher, Dr. Khurana is excited about what this kind of stem cell-based research will mean for his patients.

“My laboratory’s work is very personal,” he said. “The use of human stem cells allows us to directly connect what we do in the lab with our individual patients, and that’s very special.”

Hear more from Dr. Khurana about his Parkinson’s research in a recent panel discussion with NYSCF.

Journal Article:

The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability
Erinc Hallacli, Can Kayatekin, Sumaiya Nazeen, Xiou H. Wang, Zoe Sheinkopf, Shubhangi Sathyakumar, Souvarish Sarkar, Xin Jiang, Xianjun Dong, Roberto Di Maio, Wen Wang, Matthew T. Keeney, Daniel Felsky, Jackson Sandoe, Aazam Vahdatshoar, Namrata D. Udeshi, D.R. Mani, Steven A. Carr, Susan Lindquist, Philip L. De Jager, David P. Bartel, Chad L. Myers, J. Timothy Greenamyre, Mel B. Feany, Shamil R. Sunyaev, Chee Yeun Chung, Vikram Khurana. Cell. 2022. DOI: 10.1016/j.cell.2022.05.008

Cover image: A graphic depicts the “two faces of alpha-synuclein” and the transition from normal states (upper, organized molecular machines on a well-defined grid) to pathologic states in which there is membrane disruption, altered protein interactions, and localization (lower, chaotic, disrupted machines, darker tone). Credit: Artwork by Gergana Petrova