Researchers at McMaster have provided new insights into a key protein that could lead to earlier detection of Parkinson’s disease.
The protein alpha-synuclein behaves differently in blood and spinal fluid, according to a study that mapped the interactions of this protein directly in bodily fluids.
“We do hope this will eventually enable earlier diagnosis of Parkinson’s,” says Giuseppe Melacini, chair of McMaster’s Chemistry and Chemical Biology department.
“We’re not quite at the stage of translating this work into clinical intervention, but we hope that we have planted a few seeds that will lead to something clinically meaningful in the future.”
Until now, much of the research into diseases like Parkinson’s has focused on what happens inside the brain, but progression of the disease occurs through other parts of the body over years — and sometimes decades — before it manifests in the brain, says Rashik Ahmed, co-author of the study.
“Understanding the interactions mediated by dynamic proteins like alpha-synuclein directly in biofluids, such as blood, helps us to better explain how the pathology spreads from cell to cell and from the gut to the brain,” says Ahmed.
“It also helps us discover biomarkers that could detect the disease well before neurological symptoms develop. Crucially, being able to probe these interactions in parts of the body that are easy to access, without invasive procedures, makes the search for reliable biomarkers far more tractable.”
One of the unique aspects of this study, published in the Proceedings of the National Academy of Sciences (PNAS), is how co-first author Jinfeng Huang reproducibly stabilized biofluids – blood plasma, serum, and spinal fluid – when removed from the closed system of the human body.
“Jinfeng played a critical role in recognizing this and ultimately correcting for it, so that we can draw meaningful conclusions about the types of interactions that are occurring in these biofluids,” says Ahmed.
An important part of how Ahmed and Huang successfully mapped the interactions of alpha-synuclein with components of biological fluids was McMaster’s Nuclear Magnetic Resonance (NMR) Facility, which allows scientists to “see” how dynamic molecules behave with atomic-level precision.
While this technology can reveal how alpha synuclein interacts with components of a biofluid, it cannot readily identify what those interaction partners are, explains Ahmed.
To figure that out, the team first divided the biofluids into groups of components separated by size. By examining each fraction with NMR spectroscopy, they were able to pinpoint which groups contained interacting partners.
The team then identified specific alpha-synuclein-interacting partners through a collaboration with Madoka Akimoto from the Faculty of Health Sciences’ Centre for Microbial Chemical Biology (CMCB).
“Dr. Madoka Akimoto’s mass spectrometry analyses narrowed down our search to the most relevant proteins, without having to test thousands of proteins individually, which would be a massive amount of work,” says Huang.
Having access to hospital-supplied samples of blood and spinal fluid was also a critical component of conducting this research, says Melacini.
“This study was only possible through the state-of-the-art facilities available here at McMaster as well as through collaborations between the faculties of Science, Health Sciences, and Engineering, the McMaster Institute for Research on Aging, and Hamilton Health Sciences,” says Melacini. “It’s a tangible manifestation of what can happen when faculties work together.”
He says the methods developed by Huang and Ahmed in this study can serve as a framework for a better understanding of other highly dynamic proteins involved in neurodegeneration, including those associated with Alzheimer’s disease.