Researchers are finding new tips that could explain how Alzheimer’s disease spreads to human brains


Prions. Credit: Case Western Reserve University

Researchers at Western Reserve University studying prions — poorly folded proteins that cause lethal incurable diseases — have identified for the first time the surface features of human prions responsible for their replication in the brain.

The ultimate goal of research is to help design a stop strategy in humans and ultimately translate new approaches to working with Alzheimer’s and others .

Scientists have not yet discovered the exact cause of Alzheimer’s disease, but they largely agree that protein problems play an important role in their onset and progression. Alzheimer’s disease affects more than 6 million people in the U.S. and the Alzheimer’s Association estimates its care will cost about $ 355 billion this year.

The research was done at the Safar Laboratory of the Department of Pathology and the Center for Proteomics and Bioinformatics at Case Western Reserve University School of Medicine and the Case Western Reserve Synchrotron Center at Brookhaven Laboratories in New York. Jiri Safar, professor of pathology, neurology and neuroscience at Case Western Reserve School of Medicine, directs the work. The report, “Structurally Different External Domains Drive the Replication of Major Human Prions,” was published in the June 17 issue of PLOS Pathogens.

Prions were first discovered in the late 1980s as a biological agent that contained proteins and could be replicated in living cells without nucleic acid. The impact on public health of medical transmissions —And also animal transmissions of bovine spongiform encephalopathy (BSE “,“) prions: drastically accelerated the development of a new scientific concept of self-replicating protein.

Human prions can bind to normal proteins neighboring the brain and cause microscopic holes. In essence, they turn the brain into sponge-like structures and lead to dementia and death. These findings led to the ongoing scientific debate about whether prion-like mechanisms may be involved in the origin and spread of other neurodegenerative disorders in humans.

“Human prion diseases are possibly the most heterogeneous neurodegenerative disorders and a growing number of researches indicate that they are caused by different strains of human prions,” Safar said. “However, structural studies of human prions have lagged behind recent advances in rodent laboratory prions, in part because of their complex molecular characteristics and prohibitive biosafety requirements needed to investigate invariably fatal and non-invasive diseases. they have treatment “.

The researchers developed a new three-step process to study human prions:

  • Prions derived from the human brain were first exposed to a high-intensity synchrotron X-ray beam. This beam created hydroxyl radical species that, with brief bursts of light, selectively and progressively changed the surface chemical composition of the prion. The unique properties of this type of light source include its enormous intensity; it can be millions of times brighter than sunlight on Earth.
  • Rapid chemical modifications of prions by brief bursts of light were controlled with anti-prion antibodies. Antibodies recognize prion surface characteristics and mass spectrometry that identifies the exact sites of prion-specific strain-based differences, providing an even more accurate description of prion defects.
  • The illuminated prions were then allowed to replicate in a test tube. The progressive loss of their replication activity as the synchrotron modifies them helped to identify the key structural elements responsible for the replication and spread of prions in the brain.

“The work is a critical first step in identifying sites of structural importance that reflect differences between prions of different diagnosis and aggressiveness,” said Mark Chance, vice dean of research at the School of Medicine and co-researcher on the work. “So we can now imagine designing small molecules to bind to these sites of nucleation and replication and block human progression. disease in patients “.

This structural approach, Chance said, also provides a template on how to identify structurally important sites in poorly folded proteins in other diseases such as Alzheimer’s, which involves the spread of proteins from cell to cell in a manner similar to prions.

Researchers create the first artificial human prion

CitationResearchers find new tips that could explain how Alzheimer’s disease spreads to the human brain (2021, June 17), recovered on June 17, 2021 at hints-alzheimer-disease-human-brains. html

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