New discoveries about the role of alpha-synuclein, a well-known protein marker of Parkinson’s, may provide insights for treatment for the disease
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 (HSCI) 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.
“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 and HSCI principal faculty member Vikram Khurana, MD, PhD, chief of the Division of Movement Disorders within the Department of Neurology 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.” The team’s findings are published in Cell.
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 team’s 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.
The Khurana lab focuses on diseases caused by the mis-folding of specific proteins, including alpha-synuclein.
The main approach involves generating induced pluripotent stem cells (iPSc) from patients with neurodegenerative disease to model and observe the disease process.
“While the current work focuses on iPSC derived from patients with alpha-synuclein mutations, the human genetics analyses encompass patients with no known mutations,” says Khurana. In the future, the Khurana lab plans to broaden the iPSC modeling to this larger group of patients also. In time, iPSC technologies may facilitate targeted therapies for Parkinson’s disease, a major aim of the Khurana lab.
Paper cited: Hallacli E et al. “The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability” Cell DOI: 10.1016/j.cell.2022.05.008
Adapted from a research brief from Brigham & Women’s Hospital posted June 9, 2022.