Summary: The shape of a specific set of proteins differs in the cerebrospinal fluid of patients with Parkinson’s disease compared to those without neurodegenerative disease.
Source: ETH Zürich
Researchers at ETH Zurich have found that a set of proteins have different shapes in the cerebrospinal fluid of healthy individuals and patients with Parkinson’s disease. These could be used in the future as a new type of biomarker for this disease.
Many human diseases can be detected and diagnosed using biomarkers in blood or other bodily fluids. Parkinson’s disease is different: to date, no biomarker of this type has been used clinically to indicate this neurodegenerative disease.
A team led by Professor Paola Picotti of ETH Zurich could now help close that gap. In a study just published in the journal Structural and Molecular Biology of Naturethe researchers present 76 proteins that could serve as biomarkers for the detection of Parkinson’s disease.
Different protein structure
What makes this study special is that while the potential biomarker proteins are found in healthy and diseased individuals, their molecules are present in different forms (or structures) in each of the two groups. It is not the presence of certain proteins that indicates disease, but rather the form they have taken.
This is the first time that scientists have shown that analyzing the structures of all proteins in a body fluid can identify potential biomarkers of disease.
The next step will be to thoroughly test the markers found and verify them using larger groups of patients. This means that these candidates are not yet available for clinical diagnostics.
“But from what we’ve seen so far, they’re actually a very strong indicator of disease, so I’m confident that this idea of structural biomarkers will hold true,” says Natalie de Souza, senior scientist in the Paola Picotti’s group and one of the co-authors of the study.
Measure structural changes
In their study, the ETH Zurich researchers examined the cerebrospinal fluid of 50 healthy people and 50 patients with Parkinson’s disease. The sample material was provided to them by Dutch clinicians.
To search for biomarkers, the scientists used a specific method of measuring the proteome (i.e. the totality of all proteins in a sample), called LiP-MS, which can measure structural changes in proteins and reveal where exactly the changes are.
Conventional measurements of the proteome tend to record only the different types of proteins and their amounts, but not structural changes.
Since the structure of proteins is closely related to their functions (or, indeed, their dysfunctions), the researchers hypothesized that people with Parkinson’s disease and healthy people will show different forms of some proteins.
The current study marks the first time that researchers have successfully applied the method to a disease.
Sharpen the analysis further
In the next steps, the researchers want to further improve the LiP-MS method to amplify the signal of the biomarker and thus increase the sensitivity with which the disease can be detected.
Additionally, the scientists would like to test the new biomarkers to assess how accurately they detect Parkinson’s disease or if there might be an overlap with other neurodegenerative diseases such as Alzheimer’s disease.
In the future, the researchers also want to use their method to determine the subtypes of Parkinson’s disease and make more accurate predictions about the course of the disease.
The clinically useful diagnoses to which this might lead are still uncertain. De Souza believes that a future testing strategy could be based on antibodies that distinguish between healthy and diseased protein structures. Regular use of mass spectrometers in a clinical setting is in principle possible, she says, but would be a big challenge.
About this Parkinson’s disease research news
Author: Press office
Source: ETH Zürich
Contact: Press service – ETH Zurich
Image: Image is in public domain
Original research: Access closed.
“Global in situ analysis of the structural proteome in people with Parkinson’s disease to identify a new class of biomarkers” by Marie-Thérèse Mackmull et al. Structural and Molecular Biology of Nature
Global in situ analysis of the structural proteome in people with Parkinson’s disease to identify a new class of biomarkers
Parkinson’s disease (PD) is a widespread neurodegenerative disease for which robust biomarkers are needed. Since protein structure reflects function, we tested whether global, in situ analysis of protein structural changes provides insight into the pathophysiology of PD and could inform a new concept of structural disease biomarkers.
Using limited proteolysis–mass spectrometry (LiP–MS), we identified 76 structurally altered proteins in the cerebrospinal fluid (CSF) of individuals with PD compared to healthy donors.
These proteins were enriched in poorly regulated processes in PD, and some proteins also showed structural changes in PD brain samples.
Structural information about CSF proteins outperformed abundance information in discriminating between healthy participants and those with PD and improved the discriminatory performance of CSF measurements of the protein α-synuclein characteristic of PD .
We also present the first analysis of the interindividual variability of a structural proteome in healthy individuals, identifying the biophysical characteristics of variable protein regions.
Although independent validation is needed, our data suggest that global analyzes of the human structural proteome will guide the development of novel structural biomarkers of disease and enable the generation of hypotheses about underlying disease processes.
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