How toxic aggregates in prion diseases form and kill brain cells

Scripps' findings shed light on how brain cells die in prion diseases

Researchers showed how toxic aggregates are formed in brain cells and how to stop the process of cell death-which may also play a role in Alzheimer's and other neurodegenerative diseases in the brain
.

Prion diseases, such as Creutzfeldt-Jakob disease (CJD), are rapid and fatal dementia syndromes associated with the formation of prion protein aggregates
.

How these aggregates form and kill brain cells is still not fully understood, but a new study by scientists at Scripps Research shows that these aggregates can destroy The axon of a neuron kills the neuron.
The axon is a narrow nerve fiber through which the neuron sends signals to other neurons

The accumulation of protein in axons, as well as other signs of axon swelling and dysfunction, are also early features of other neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease
.

"Science Advances" (Science Advances) magazine reported that discovering how these prions gather in axons and how to inhibit them may ultimately have far more significance than prion diseases

"We hope that these findings will lead to a better understanding of prions and other neurodegenerative diseases, as well as new strategies to treat them," said Dr.
Sandra Encalada, the senior author of the study, who is in the Department of Molecular Medicine at the Scripps Research Center.
Associate Professors Arlene and Arnold Goldstein
.

In their study, the researchers carefully observed the mutant pathogenic copies of the prion disease protein PrP.
They formed a large number of clusters in the axons of neurons, rather than in the main cell bodies of neurons
.

The formation of these aggregates is accompanied by signs of axon dysfunction and ultimately leads to neuronal death

The researchers also discovered a key protein complex that is responsible for guiding PrP to axons and causing aggregation associated with axon swelling
.

They demonstrated that by silencing any of these proteins, they can inhibit the formation of aggregates and protect neurons from damage and death

Fragile axons

Creutzfeldt-Jakob disease is the most common prion disease in humans, with about one case per million people in the world every year
.

Most cases are thought to be spontaneously produced when PrP changes in the brain in some way and starts to accumulate

In this study, Encalada's team used mouse brain cells containing mutant PrP and film technology under the microscope to study the initial accumulation of PrP in axons
.

The axon of a neuron is usually very long compared to its main body (the body), and it has been found that when its fragile transport essential molecules and waste removal system are destroyed, the axon has a unique fragility

The normal function of PrP in neurons has been unclear, but this protein seems to be normally secreted from somatic cells and axons through sac-like containers called vesicles, and is sometimes recovered or degraded in axons.
Waste
.

The researchers found in their experiments that the mutant PrP produced in somatic cells is also largely encapsulated in vesicles, which move to axons along railroads called microtubules

This movement involves a somewhat complicated vesicle transport system.
The researchers observed that the system shunts most of the PrP to the axons, where the vesicles containing PrP gather and merge
.

In this case, the mutated PrP formed large aggregates—encalada called them endomorphs—and the axons could not get rid of these aggregates

Researchers have also discovered a way to combat the formation of endoderm
.
They identified four proteins, Arl8, Kinesin 1, Vps41, and SKIP, which are responsible for guiding prp-containing vesicles to axons, bringing them to the body cell, and merging them with other prp-containing vesicles to trigger Aggregate formation
.
When they silenced any of these proteins, far fewer prp-containing vesicles entered the axons, the axons showed little or no signs of aggregation, the neurons functioned normally or almost normally, and survived normally.
Brain cells are just as good
.

This result shows a fascinating possibility that prion diseases, as well as many other protein-aggregating diseases in the brain, can be achieved by at least temporarily interrupting the transport of vesicle-encapsulated, aggregated proteins to axons.
To prevent or treat
.

Encalada said: "We are very keen to discover molecules that can inhibit this aggregation formation pathway, and to study the role of these inhibitors in animal models of prions and other neurodegenerative diseases
.
"