Uncovering the mystery of the origin of Alzheimer’s disease: Is the replication of prions in the human brain the culprit?
In 1958, Francis Crick proposed the famous “Central Dogma”, thereby constructing a large framework for the transmission of biological genetic information, namely “DNA→RNA→Protein”. Of course, as a theory, the central principle is often questioned and misunderstood, e.g., RNA can also be written back to DNA, and the self-replication of prions.
Prion is a misfolded protein that can generate amyloid fibril clumps. In truth, a prion is neither a virus or even a type of organism in the strictest sense, but rather an infectious agent that lacks nucleic acid and is entirely made up of protein.
The protein aggregates formed by prions are the chief culprit in mammalian neurodegenerative diseases (such as Alzheimer’s disease). The reason why prions are so deadly is that they can transfer the wrong conformation to the otherwise healthy protein, causing cell function imbalance. More importantly, there is currently no effective way to treat prion diseases.
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.
This study discovered for the first time the surface characteristics of human prions replicating in the brain. 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.
Alzheimer’s disease (AD) 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. In contemporary society, as the average life expectancy of human beings increases, the prevalence of Alzheimer’s disease is also rising.
Scientists have yet to pinpoint the exact etiology of Alzheimer’s disease, but they do believe that protein abnormalities have a role in the onset and progression of the disease.
Human prions can form tiny holes in the brain when they attach to nearby normal proteins. They transform the brain into a spongy structure, resulting in dementia and death. These discoveries have prompted a debate in the scientific community about whether prion-like mechanisms have a role in the onset and spread of human neurodegenerative disorders.
According to Professor Jiri Safar, a neuroscientist at Case Western Reserve School of Medicine and the study’s corresponding author, human prion diseases are among the most heterogeneous neurodegenerative diseases, and a growing body of research suggests that they are caused by different strains of human prions. However, structural investigations of human prions have lagged behind recent discoveries in animal disease models due to a number of issues.
In this study, the research team developed a novel three-step process for studying human prions:
1. Human brain-derived prions were exposed to a high-intensity synchronized X-ray beam for the first time, which produced hydroxyl radicals that selectively and progressively altered the surface chemistry of the prion through short bursts of light. The unique properties of this light source include its tremendous intensity, which is millions of times brighter than the light that travels from the sun to earth.
2. Rapid chemical modification of prions by short pulses of light monitored with anti-prion antibodies. Antibodies recognize the surface antigens of prions, while mass spectrometry identifies the specific location of prion specificity, providing a more accurate description of prion defects based on strain differences.
3. Allowing the replication of luminous prions in the test tube. The replication activity of prions is gradually lost when they are modified by the synchrotron, which helps in identifying the key structural elements responsible for prion replication and reproduction in the brain.
The research team identified the detailed structural differences of the main human prions — sCJD MM1, MM2, and VV2, using the methods described above. Two complementary synchronous hydroxyl radical footprinting techniques — mass spectrometry and conformational dependent immunoassay (CDI) were used to create these prions, as well as a set of antibodies that have been labeled with europium.
The findings reveal that the structure of different prions varied significantly. Synchrotron-produced hydroxyl free radicals eventually restrict their propagation in a strain- and structure-specific way. Furthermore, when sporadic Creutzfeldt-Jakob disease (sCJD) prions are exposed to solvents, the transmission rate is largely dictated by the strain-specific structure and organization of the exterior domain of human prion particles.
All in all, 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. 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.