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Protein patterns may indicate Parkinson’s disease

Protein patterns may indicate Parkinson’s disease

Summary: The shape of a specific set of proteins differs in the spinal fluid of patients with Parkinson’s disease compared to those without the neurodegenerative disease.

Source: ETH Zurich

ETH Zurich researchers have discovered that a set of proteins have different forms in the spinal fluid of healthy individuals and patients with Parkinson’s disease. In the future, they could be used as a new type of biomarker for this disease.

Many human diseases can be detected and diagnosed using biomarkers in blood or other body fluids. Parkinson’s disease is different: to date, there is no such biomarker used in the clinic to indicate this neurodegenerative disease.

A team led by Professor Paola Picotti from ETH Zurich could now help close this gap. In a study just published in the journal Natural structural and molecular biologyresearchers 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, although potential biomarker proteins are found in both 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 the form they have taken.

This is the first time scientists have shown that structural analysis of all proteins in body fluid can identify potential biomarkers for disease.

The next step will be thorough testing of the found markers and their verification using larger groups of patients. This means that these candidates are not yet available for clinical diagnosis.

“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 work,” says Natalie de Souza, a senior scientist in Paola Picotti’s group and one of the study’s co-authors.

Measurement of structural changes

In their study, ETH Zurich researchers examined the cerebrospinal fluid of 50 healthy individuals and 50 patients with Parkinson’s disease. The sample material was given to them by Dutch clinicians.

In their search for biomarkers, the scientists used a specific method for measuring the proteome (ie, the totality of all proteins in a sample), called LiP-MS, which can measure structural changes in proteins and reveal exactly where the changes are located.

Conventional proteome measurements tend to record only different types of proteins and their amounts, but not structural changes.

Because the structure of proteins is closely related to their functions (or, actually, dysfunctions), researchers hypothesized that people with Parkinson’s disease and healthy individuals would show different forms of some proteins.

It is not the presence of certain proteins that indicates disease, but the form they have taken. Image is in the public domain

This study is the first time researchers have successfully applied this method to a disease.

Sharpening the analysis further

In the next steps, the researchers want to further improve the LiP-MS method to amplify the biomarker signal and thus increase the sensitivity with which the disease can be detected.

Moreover, scientists would like to test the new biomarkers to assess how specifically they detect Parkinson’s disease or whether there is overlap with other neurodegenerative diseases such as Alzheimer’s disease.

In the future, the researchers also want to use their method to determine subtypes of Parkinson’s disease and make more accurate predictions about the course of the disease.

It is still uncertain what clinically useful diagnostics this may lead to. De Souza speculates that a future testing strategy could be based on antibodies that would distinguish between healthy and diseased protein structures. Regular use of mass spectrometers in a clinical setting is in principle possible, she says, but it would be a big challenge.

See also

This shows neurons in the lateral habenula

About this Parkinson’s disease research

Author: Press Office
Source: ETH Zurich
Contact: Press Office – ETH Zurich
picture: Image is in the public domain

Original Research: Closed access.
Global, in situ analysis of the structural proteome in individuals with Parkinson’s disease to identify a new class of biomarkers” by Marie-Therese Mackmull et al. Natural structural and molecular biology


Abstract

Global, in situ analysis of the structural proteome in individuals with Parkinson’s disease to identify a new class of biomarkers

Parkinson’s disease (PD) is a prevalent 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 can 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 are enriched in processes that are misregulated in PD, and some proteins also showed structural changes in PD brain samples.

CSF protein structural information outperformed abundance information in discriminating between healthy participants and those with PD and improved the discriminatory performance of CSF measures of the signature PD protein α-synuclein.

We also present the first analysis of inter-individual variability of the structural proteome in healthy individuals, identifying biophysical features 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 diseases.



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