Parkinson’s disease is on the rise as average ages increase, but treatment is often delayed through difficulties in distinguishing its early symptoms from other conditions. The discovery that proteins in a patient’s spinal fluid have distinctive structures could address this problem. It could also increase our understanding of the causes of the disease, improving the chances of finding better treatments.
Professor Paola Picotti of ETH Zurich led a team comparing a suite of proteins found in the cerebral fluid of 50 individuals with early-stage Parkinson’s and an equal number of age-matched healthy controls. The team reports that 76 proteins – some previously linked to Parkinson’s Disease – have notably different structures between the two groups and could serve as a biomarker for the disease.
Diseases can affect protein structures by triggering them to fold in undesirable ways, bind to small molecules, or interact with other proteins.
Although no biomarker for Parkinson’s is in clinical use, quite a few have been proposed in recent years. The reliability of these remains uncertain, however – and it is here that Picotti believes the new work has an advantage. Since the proteins exist in both sick and healthy individuals, comparing their forms may be easier than looking for changes in abundance, as is usually done for disease biomarkers.
When combining their test with another biomarker currently under investigation, the authors found each had 75 percent reliability on its own, but the two combined reached an impressive 91 percent.
Global analysis of protein structures has never been used as a disease biomarker before; the authors hope it may prove suitable for other diseases as well.
There is still a long way to go, however. Larger sample sizes will be needed to confirm the reliability, along with testing people with other diseases to make sure they can be distinguished from each other.
With so many potential proteins to choose from, it will also be necessary to select the most reliable subset to use. "But from what we've seen so far, they're actually a very strong indicator for the disease. So I'm confident that this idea of structural biomarkers will bear out," study co-author Professor Natalie de Souza said in a statement.
Another important question is how early in the disease’s development protein changes reach the point where the limited proteolysis–mass spectrometry (LiP-MS), the structural measuring system the researchers used, can detect them.
The relationship between protein structure and function is well established, and it is known that structure changes with disease. The protein α-synuclein is known to form deposits called Lewy bodies in the brains of 90 percent of Parkinson’s patients.
Nevertheless, the detail of the proteins affected, and the nature of the changes, could shed light on the causes of Parkinson’s and how it relates to other neurodegenerative diseases. Ideally, the proteins might also make for more accurate predictions of how an individual’s condition will progress.
Mass spectrometry is expensive, however, which could hinder efforts to use protein structure as a mass screening technique.
The paper is published in Nature Structural and Molecular Biology