Researchers discover key Parkinson’s disease protein ‘switch’

The graphic depicts “two sides of alpha-synuclein” and the transition from normal states (upper molecular machines organized on a well-defined network) to pathological states in which there is membrane perturbation and altered protein interactions and localization (lower, chaotic, discontinuous machines, darker tone). Credit: Artwork by Girjana Petrova

Researchers have discovered a new function of alpha-synuclein, a known protein marker for Parkinson’s disease, that is relevant to treating the disease.

When many people think of Parkinson’s disease, they associate it with Michael J. Fox. It may have just come to prominence because it was diagnosed at such a young age that Parkinson’s disease is actually relatively common. In fact, there are approximately one million Americans living with it, and about 60,000 more are diagnosed each year, according to the Parkinson’s Foundation, as well as other notable people such as George HW Bush, Muhammad Ali, Billy Connolly, Neil Diamond, and Billy. Graham.

Fortunately, scientists are working hard, and looking to understand the disease, in order to develop treatments and treatments. New progress on this front has been made in new research that has revealed key insights into a key protein.

One of the hallmarks of Parkinson’s disease (PD) is a buildup of a protein in the brain known as alpha-synuclein. For more than two decades, alpha-synuclein has been a focal point of interest for researchers, clinicians, and drug makers interested in PD. But the function of alpha-synuclein is not well understood. A new study led by researchers at Brigham and Women’s Hospital, the Harvard Stem Cell Institute and the Broad Institute at Harvard and[{” attribute=””>MIT shines new light on the role of alpha-synuclein, uncovering a new function for the protein with relevance for PD and related conditions. Findings will be published today (June 9, 2022) in the journal Cell.

“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 corresponding author Vikram Khurana, MD, PhD, chief of the Division of Movement Disorders within the Department of Neurology at the Brigham and Harvard Medical School, and a principal investigator within the Ann Romney Center for Neurologic Diseases at the Brigham. “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.”

Khurana and colleagues’ initial leads came from yeast and fruit fly models of alpha-synuclein toxicity and were substantiated through studies of human cells, patient-derived neurons, and human genetics. The team found that the very same part of the alpha-synuclein protein that interacts with vesicles also binds to “P-body” structures, machinery in the cell that regulates the expression of genes through messenger RNAs (mRNAs). In induced pluripotent stem cell-derived neurons generated from PD patients with alpha-synuclein gene mutations, the physiologic structure and function of the P-body was lost, and mRNAs were abnormally regulated. The same occurred in tissue samples from postmortem brains from patients. Human genetic analyses supported the disease-relevance of these findings: patients who accumulate mutations in P-body genes appeared to be at higher risk for PD.

The authors describe alpha-synuclein as a “toggle switch” that regulates two very distinct functions: transport of vesicles and gene expression. In disease states, the balance is broken. The findings have potential implications for development of treatments for PD. The authors note that more clarity is needed on which of the P-body machinery components might be the best targets for a therapeutic intervention. Ongoing genetic studies aim to identify which patients might be best suited for such an intervention, and how much this newly discovered pathway contributes to risk of the disease and disease progression in PD patients at large.

“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,” said lead author Erinc Hallacli, PhD, of the Department of Neurology and the Ann Romney Center for Neurologic Diseases at the Brigham. “This paper provides important information to fill our knowledge gaps about this protein, which may be beneficial for clinical translation.”

Reference: “The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability” 9 June 2022, Cell.
DOI: 10.1016/j.cell.2022.05.008

Funding: Khurana is a NYSCF Stem Cell Robertson Investigator and an investigator of the Aligning Science Across Parkinson’s Initiative. He is a George C. Cotzias Fellow of the American Parkinson’s Disease Association. This work was also supported by the Brigham Research Institute Director’s Transformative Award, Department of Defense (W81XWH-19-1-0695), Human Frontier Science Program (LT000717/2015-L) and the National Institutes of Health (R21NS112858, R21NS112858 and R01NS109209). Additional funding support was provided by Alzheimer’s Research UK (ARUK), the Biomarkers Across Neurodegenerative Diseases Grant from the Alzheimer’s Association, Koerner New Scientist Program from the Koerner Family Foundation, Michael J. Fox Foundation for Parkinson’s Research (MJFF) and the Weston Brain Institute (Weston) (BAND-19-615151).

Disclosures: Khurana is a co-founder of and senior advisor to Dacapo Brainscience and Yumanity Therapeutics, companies focused on central nervous system diseases. Co-authors Chee Yeun Chung and Xin Jiang contributed to this work as employees of Yumanity Therapeutics.

Leave a Reply

Your email address will not be published.