Summary: The Parkinson’s-associated protein alpha-synuclein appears to act as a “toggle switch” that helps control vesicle transportation and gene expression. In a diseased state, this delicate balance is broken. The findings have implications for the development of new treatments for Parkinson’s disease.
Source: Brigham and Women’s Hospital
One of the hallmarks of Parkinson’s disease (PD) is the accumulation in the brain of a protein known as alpha-synuclein. For more than two decades, alpha-synuclein has been a focal point of attention for researchers, clinicians and drug makers interested in PD. But alpha-synuclein’s function is not well understood.
A new study led by investigators at Brigham and Women’s Hospital, Harvard Stem Cell Institute and the Broad Institute of Harvard and 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 are published in 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.”
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.
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).
The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability
αS toxicity linked to P-bodies through yeast, fly, and human genetics
Physiologic binding of αS N terminus to either membranes or P-body decapping module
Pathologic αSyn accumulation disrupts the decapping module in PD neurons and brain
Pathologic αSyn disrupts mRNA stability in PD iPSC neurons
Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson’s disease (PD).
Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage.
The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain.
Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions.
Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.