How toxic aggregates form and kill brain cells in prion disease
Scripps Research discovery reveals how brain cells die in prion disease
Researchers show how toxic aggregates form inside brain cells and how to block the process of cell destruction, which may also be at work in Alzheimer’s and other neurodegenerative diseases.
Prion diseases, such as Creutzfeldt-Jakob disease (CJD), are rapidly progressive fatal dementia syndromes associated with the formation of aggregates of the prion protein, PrP. How these aggregates form inside and kill brain cells has never been fully understood, but a new study from scientists at Scripps Research suggests that aggregates kill neurons by damaging their axons, the narrow nerve fibers across. which they send signals to other neurons.
Accumulation of protein aggregates in axons, along with axonal swelling and other signs of dysfunction, are also early features of other neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. The discovery of how these prion aggregates form in axons and how to inhibit them, reported in Scientists progress, may ultimately have a meaning that goes far beyond prion disease.
“We hope that these results will lead to a better understanding of prion and other neurodegenerative diseases, as well as new strategies to treat them,” says study lead author Sandra Encalada, PhD, Arlene and Arnold Goldstein, associate professor in the Department of Molecular Medicine at Scripps Research.
In their study, the researchers observed disease-causing mutant copies of the prion-disease protein PrP up close, forming large aggregates in the axons of neurons, but not in the main cell bodies of neurons. The formation of these aggregates was followed by signs of axonal dysfunction and ultimately neuronal death. Scientists have found evidence that the waste disposal processes of neurons are normally able to handle such aggregates when they are in or near the main cell bodies of neurons, but are much less able to handle it. do when the aggregates build up far in the axons.
The researchers also identified a complex of key proteins as being responsible for directing PrP in axons and causing aggregation associated with large axonal swellings. They have shown that by silencing one of these proteins, they can prevent aggregate formation and protect neurons from damage and death.
CJD is the most common human prion disease, occurring at a rate of about one case per million people per year worldwide. It is believed that most cases occur spontaneously when PrP is changed in some way in the brain and begins to aggregate. Since these aggregates develop through a chain reaction process that attracts healthy copies of PrP, they can transmit CJD in rare cases, such as during a corneal transplant, from person to person. . About 15 percent of cases are inherited, caused by mutations that make PrP more likely to aggregate. Prion disorders occur in other mammals and are believed to be due to similar toxic aggregations of PrP proteins from different species.
In the study, the Encalada team used mouse brain cells containing mutant PrP, along with microscopic cinema techniques, to study the initial accumulation of PrP aggregates in axons. A neuron’s axon is often very long compared to its main body, the soma, and has been shown to be particularly vulnerable to disruption of its delicate systems for transporting essential molecules and removing waste.
The ordinary function of PrP in neurons has never been clear, but the protein appears to be normally secreted, via bag-shaped vessels called vesicles, from the soma and axon, where it sometimes returns to be recycled or degraded as waste. The researchers found in their experiments that the mutant PrP produced in soma is also largely encapsulated in vesicles that travel through the axon along railroad tracks called microtubules.
This movement involves a somewhat complex vesicle trafficking system, and the researchers observed that this system derives much of the PrP far into the axons, where the PrP-containing vesicles come together and fuse. The mutant PrP in this situation forms large aggregates – Encalada calls them endogresomes – which the axons cannot get rid of. The aggregates cause axonal swelling and other signs of dysfunction, including a reduction in neuronal calcium signaling and ultimately a much faster rate of neuronal death than neurons with normal PrP.
Researchers have also found a way to counter the formation of endogresomes. They identified four proteins, Ar18, kinesin-1, Vps41, and SKIP, which are responsible for directing PrP-containing vesicles into axons, transporting them far into the soma, and fusing them with other vesicles containing PrP. PrP to trigger the formation of aggregates. When they silenced one of these proteins, far fewer PrP-containing vesicles entered the axons, the axons showed little or no signs of aggregation, and the neurons functioned normally or almost normally. and survived as well as normal brain cells.
The results indicate the tantalizing possibility that prion diseases, and possibly many other diseases of the protein aggregates of the brain, can be prevented or treated by at least temporarily disrupting the trafficking process that brings the proteins encapsulated into vesicles and subject. to aggregates in axons.
“We are very excited to discover molecules capable of inhibiting this pathway of aggregate formation and to study the effects of these inhibitors in animal models of prions and other neurodegenerative diseases,” says Encalada.
Reference: “Endosomal sorting drives the formation of axonal prion protein endoggresomes” by Romain Chassefeyre, Tai Chaiamarit, Adriaan Verhelle, Sammy Weiser Novak, Leonardo R. Andrade, André DG Leitão, Uri Manor and Sandra E. Encalada, December 22, 2021, Science.
DOI: 10.1126 / sciadv.abg3693
“Endosomal Sorting Drives the Formation of Axonal Prion Protein Endoggresomes” was co-authored by Romain Chassefeyre, Tai Chaiamarit, Adriaan Verhelle, André Leitão and Sandra Encalada, all of Scripps Research; and Sammy Weiser Novak, Leonardo Andrade and Uri Manor, from the Salk Institute for Biological Studies.
The research was funded by the National Institutes of Health (R01AG049483) and others.