Uncovering the mystery of the origin of Alzheimer's disease: Is the replication of prions in the human brain the culprit?

Written | nagashi editor | Wang Duoyu typesetting | Water written in 1958, Francis Crick proposed the famous central law, thus constructing a large framework for the transmission of biological genetic information, namely "DNA→RNA→protein"
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Of course, as a theory, the central principle is often questioned and misunderstood, such as RNA can also be written back to DNA, and the "self-replication" of prions
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Prion is a type of misfolded protein that can form aggregates of amyloid fibrils
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In fact, in a strict sense, a prion is not a virus, or even a kind of organism, but an infectious factor that does not contain nucleic acid but is composed only of protein
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The protein aggregates formed by prions are the chief culprit in mammalian neurodegenerative diseases (such as Alzheimer's disease)
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The reason why prions are so deadly is that they can transfer the wrong conformation to the otherwise healthy protein, causing cell function imbalance
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More importantly, there is currently no effective way to treat prion diseases
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Recently, researchers from Case Western Reserve University in the United States published a research paper titled: Structurally distinct external solvent-exposed domains drive replication of major human prions in the journal PLOS Pathogens
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This study has discovered for the first time the surface features of human prions replicating in the brain
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The ultimate goal of this research is to help design a strategy to prevent human prion diseases and eventually apply the new method to the treatment of Alzheimer's and other neurodegenerative diseases
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Alzheimer's disease (AD), commonly known as "Alzheimer's disease", is a type of central nervous system degenerative disease that mainly occurs in the elderly and is characterized by progressive cognitive dysfunction and behavioral impairment
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In contemporary society, as the average life expectancy of human beings increases, the prevalence of Alzheimer's disease is also rising
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In China alone, the incidence of Alzheimer’s disease among people over 65 years of age is 5%, and every 10 years of age increases, the incidence increases by 5%.
That is to say, among people aged 85 years, every 2-3 There is one patient with Alzheimer's disease
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Unfortunately, until now, scientists have not discovered the exact cause of Alzheimer's disease, but basically agree that protein abnormalities play a role in the emergence and development of Alzheimer's disease
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Human prions can bind to neighboring normal proteins in the brain and create tiny holes
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Essentially, they turn the brain into a spongy structure and cause dementia and death
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These findings have sparked an ongoing scientific debate about whether prion-like mechanisms are related to the origin and spread of human neurodegenerative diseases
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Professor Jiri Safar, a neuroscientist at Case Western Reserve School of Medicine, the corresponding author of this study, said: Human prion diseases are the most heterogeneous neurodegenerative diseases, and more and more studies have shown that they are caused by different humans.
Caused by a prion strain
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However, many factors have caused the structural research of human prions to lag behind the latest advances in animal experiments
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In this study, the research team developed a new three-step process for studying human prions: 1.
The prions derived from the human brain were exposed to high-intensity synchronized X-ray beams for the first time
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This light beam produces hydroxyl radicals, which selectively and gradually change the surface chemical composition of prions through a short burst of light
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The unique characteristics of this light source include its immense intensity-it is millions of times brighter than the light from the sun to the earth
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2.
Use anti-prion antibodies to monitor the rapid chemical modification of prions by short-pulse light
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Antibodies can identify the surface features of prions, while mass spectrometry can identify specific locations of prions.
Based on the differences in strains, it provides a more accurate description of prion defects
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3.
Let the glowing prion replicate in the test tube
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As the synchrotron modifies prions, their replication activity is gradually lost, which helps to identify the key structural elements responsible for the replication and reproduction of prions in the brain
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The different age of onset and disease duration of sCJD MM1, MM2 and VV2 prions Based on the above methods, the research team reported the detailed structural differences of the main human prions-sCJD MM1, MM2 and VV2.
These prions are complemented by two kinds of Simultaneous hydroxyl radical footprinting technology-mass spectrometry, conformation-dependent immunoassay (CDI) and a set of europium-labeled antibodies were measured
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The demographics, molecular characteristics and synchrotron hydroxyl radical inactivation of different sCJD prions showed that different prions have major differences in their structure and organization.
The hydroxyl free radicals produced by synchrotrons are based on a strain and structure.
The specific way gradually inhibits its spread
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In addition, the transmission rate of sporadic Creutzfeldt-Jakob disease (sCJD) prions is mainly determined by the strain-specific structure and organization of the external domain of human prion particles that control the transmission rate when exposed to the solvent.

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Simultaneous hydroxyl radical footprinting technology on the inactivation kinetics of SCJD MM1, MM2 and VV2 prions.
Professor Mark Chance, the co-investigator of the study, said: “This work is to identify the structure that reflects the differences between prions of different diagnoses and aggressiveness.
The critical first step for important sites
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Therefore, we can now envision designing small molecules to bind to these nucleation and replication sites and prevent the progression of human prion diseases in patients
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"sCJD MM1, MM2 and VV2 prions In summary, this study shows that by analyzing the structural characteristics of human prion strains, subtle changes in surface domains play a key role in determining the infectivity, reproduction rate, and targeting of specific brain structures of human prions.

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Not only that, the research also provides a new template for identifying important structural sites on misfolded proteins in other neurodegenerative diseases, so as to guide the development of new treatment methods for neurodegenerative diseases
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The link to the paper: https://doi.
org/10.
1371/journal.
ppat.
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