Early Parkinson’s Detection Technique Validated in Prion Animal Models, Study Shows

Early Parkinson’s Detection Technique Validated in Prion Animal Models, Study Shows

The early detection of diseases characterized by protein misfolding and aggregation, such as Parkinson’s disease, moved one step closer by the validation in animal models of a sensitive technique to capture and analyze misfolded and aggregated proteins in the blood quickly and efficiently.

The technique was validated by showing that prions — a misfolded protein that causes prion disease — can be captured, isolated, analyzed, and transferred between species, a study has shown. 

The study, “Enhanced detection of prion infectivity from blood by preanalytical enrichment with peptoid-conjugated beads,” was published in the journal PLOS ONE

Parkinson’s disease is caused by the damage or death of dopamine-producing nerve cells (neurons) in a region of the brain that controls balance and movement. 

A hallmark of the disease is the accumulation of a misfolded form of a protein called alpha-synuclein, a protein typically located near the tips of nerve cells and associated with the regulation of dopamine release.

To function properly, a protein must fold into a specific shape. However, when alpha-synuclein does not fold properly or misfolds, it clumps together to form plaques in the brain, causing cell damage and death. 

A misfolded protein is also the causative agent in transmissible spongiform encephalopathies or prion diseases. The most famous prion disease is bovine spongiform encephalopathy (BSE) — otherwise known as “mad cow disease” — where misfolded proteins, called prions, from cows in the food chain or infected people trigger other proteins in the brain to misfold and aggregate. 

The outbreak of BSE in European cattle and several hundred associated cases in humans in the late 1980s has spawned efforts to find methods to detect the very low levels of prions in the blood of infected people.

One method that has been successful, called the misfolded protein assay (MPA), involved selectively capturing prions using molecules that mimic the parts of the prion that bind together to form aggregates.

These mimicking molecules — known as peptoids — are composed of modified versions of the naturally occurring amino acids (building blocks) of prion proteins.

The peptoids are fixed to magnetic beads (PSR1) which can be mixed, then easily isolated from blood and tested for prions. One of the advantages of MPA over other tests is that it can analyze large numbers of samples quickly and for less cost.

The MPA technique was used to successfully identify prions in a patient with prion disease when other tests failed. In addition, the utility to capture and analyze prions extends beyond prion diseases to other conditions characterized by protein misfolding, such as Parkinson’s, and may provide a means to diagnose the disease years before symptoms arise.

Before MPA can be used in humans, efficacy must be determined in animal models, so researchers designed a study to test the reliability and sensitively of MPA to detect prions using mouse and hamster models of prion disease.

Brain tissue from hamsters bred to develop prion disease was injected into 40 healthy hamsters, and five control hamsters were inoculated with brain tissue from non-infectious hamsters. 

Blood was withdrawn from the hamsters before and after the appearance of prion disease symptoms, namely ataxia (lack of muscle control), loss of appetite, and poor grooming. 

The PSR1 magnetic beads were mixed with these blood samples and were washed to remove extra proteins. The washed beads were then injected into a special breed of mice — Tg(SHaPrP) — that expressed the normal form of hamster prion protein. If infectious misfolded prions were captured by the beads, they would trigger the normal form of hamster prion protein to misfold in the mice and lead to prion disease. 

The results demonstrated that in mice that were inoculated with beads mixed with blood from hamsters with prion disease symptoms, nearly all of the mice (25 of 28 injected) developed prion disease. Prion disease was confirmed by examining mice brain tissue under a microscope. 

In contrast, mice injected with beads mixed with non-symptomatic hamster blood (or controls) did not develop signs of prion disease. 

“We therefore conclude that PSR1 beads highly efficiently capture prion infectivity from plasma from presymptomatic and symptomatic cases and are able to transmit infectivity to Tg(SHaPrP) mice,” the researchers wrote. “We found that the readout of the peptoid-based misfolded protein assay (MPA) correlates closely with prion infectivity in vivo, thereby validating the MPA as a simple, quantitative, and sensitive surrogate indicator of the presence of prions.” 

Ronald Zuckermann, PhD, study co-author and senior scientist at the Lawrence Berkeley National Laboratory Molecular Foundry, in Berkeley, California, noted in a press release, “Our peptoid beads have the ability to detect the misfolded proteins that act as infectious agents, so it could have a significant impact in the realm of prion diseases, but we have also shown that it can seek out the large aggregated proteins that are the disease agents in Alzheimer’s and Parkinson’s diseases, among others.” 

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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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