Discovery illuminates how brain cells die in prion diseases


Neurons grown in culture that express the mutant prion protein (cyan) that causes prion disease in humans. These neurons display swollen axons containing toxic mutant prion protein aggregates. Chasse feyre et al. We have identified genes that explain the formation of these aggregates and have shown that by reducing their function, they can inhibit the formation of aggregates and prevent neurological dysfunction. Credits: Adriaan Verhelle and Yin Wu (Scripps Research)

Prion diseases such as Creutzfeldt-Jakob disease (CJD) are fast-moving, deadly dementia syndromes associated with the formation of aggregates of the prion protein PrP. Although it is not fully understood how these aggregates form and die in brain cells, a new study by scientists at Scripps Research shows that aggregates signal thin to other neurons. It has been suggested to kill neurons by damaging the axons, which are nerve fibers.

Accumulation of protein aggregates AxonIt is also an early feature of other neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, along with signs of axonal swelling and other dysfunction.Discovery of these methods Prion Aggregates are formed of axons, and the method of inhibiting them is Science AdvancesIn the end, it can be of much greater importance than prion disease.

“We hope that these discoveries will lead to a better understanding of prions and other neurodegenerative diseases and lead to new strategies for treating them,” said senior authors of the study, Dr. Sandra Enkarada, Arlene and Arnold.・ Associate Professor Goldstein said. Department of Molecular Medicine, Scripps Research.

Researchers in their study closely observe the disease-causing copy of a variant of the prion disease protein PrP, which forms large aggregates in neuronal axons but not in the neuronal major cell bodies. Did. The formation of these aggregates was followed by signs of axonal dysfunction, eventually leading to neuronal cell death. Scientists say that the neuronal waste disposal process can usually deal with such aggregates when they are inside or near the neuronal major cell bodies, but the aggregates accumulate far away in the axons. I found evidence that I couldn’t deal with it.

Researchers have also identified that a major protein complex is responsible for inducing PrP to axons and causing aggregation associated with large axon swelling. They have demonstrated that silencing any of these proteins can suppress the formation of aggregates and protect neurons from damage and death.

Vulnerable axons

CJD is the most common human prion disease, occurring in about 1 in 1 million people worldwide annually. In most cases, PrP is thought to occur spontaneously when it changes in some way in the brain and begins to aggregate. These aggregates grow by a chain reaction process that takes up a healthy copy of PrP, which can, in rare cases, infect one person to another with CJD, for example during corneal transplant surgery. Approximately 15% of cases are hereditary and are due to mutations that increase the likelihood of PrP aggregation. Prion disorders occur in other mammals and are thought to be due to similar toxic aggregation of PrP proteins of different species.

In this study, Enbody’s team used mouse brain cells containing mutant PrP in conjunction with microscopic cinematography to study the initial accumulation of PrP aggregates in axons. Neuronal axons are often very long against their main body, somatic cells, and can be uniquely vulnerable to the destruction of delicate systems for transporting essential molecules and removing waste products. I already know.

Although the normal function of PrP in neurons has not been elucidated so far, proteins are usually secreted from somatic cells and axons via sac-like vessels called vesicles and recycled or degraded as waste. You may. Researchers have also found in experiments that mutant PrP produced by somatic cells is also largely encapsulated in vesicles that travel to axons along railroads called microtubules.

This movement involves a rather complex vesicle transport system, where researchers have observed that much of PrP is shunted into axons, where vesicles containing PrP gather and fuse. Mutant PrP in this situation forms large aggregates that axons cannot remove — Enbodys call them endogresomes. Aggregates provide signs of other dysfunctions, including axonal swelling and decreased neuronal calcium signaling, and ultimately, much faster neuronal mortality compared to neurons with normal PrP. Brings.

Researchers have also found ways to combat endogresome formation. They identified four proteins: Arl8, kinesin-1, Vps41, and SKIP. These proteins direct PrP-containing vesicles toward axons, carry them deep into somatic cells, and bind to other PrP-containing vesicles to cause aggregate formation. When they silenced any of these proteins, much less PrP-containing vesicles enter the axons, the axons show little or no signs of aggregation, and the neurons function normally or almost normally. Survived like normal brain cells.

The results show that it can be intriguing Prion disease, And probably many others protein-Brain aggregate disease can be prevented or treated by at least temporarily interrupting the transport process that carries proteins that are prone to aggregate encapsulated in vesicles to axons.

“We are very keen to discover molecules that can inhibit this aggregate formation pathway and to study the effects of such inhibitors in prions and other animal models. Neurodegenerative disease“Enkalada says.

“Endosome sorting promotes the formation of axonal prion protein endosomes” was co-authored by Romain Chassefeyre, Tai Chaiamarit, Adriaan Verhelle, André Leitão, Sandra Encalada, all by Scripps Research. Sammy Weiser Novak, Leonard Andrade, Uri Manor of the Salk Institute.

Viral infections can promote neurodegeneration

For more information:
Romain Chassefeyre et al, Endosome sorting promotes the formation of axonal prion protein endosomes, Science Advances (2021). DOI: 10.1126 / sciadv.abg3693..

Quote: Discovery was obtained from on December 22, 2021 for prion disease (December 22, 2021). Reveals how brain cells die in

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