Prion diseases are a family of rare progressive neurodegenerative disorders that affect both humans and animals. They are associated with the formation of aggregates of the prion protein, PrP. How these aggregates form within and kill brain cells has not been fully understood. However, researchers at Scripps Research now report that the aggregates kill neurons by damaging their axons.

Their findings are reported in Science Advances in a paper titled, “Endosomal sorting drives the formation of axonal prion protein endoggresomes.”

Axons are very thin nerve fibers that carry nerve impulses away from a neuron to another neuron. Axon loss is an early sign of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s.

In the study, the researchers used mouse brain cells containing mutant PrP, along with microscopic motion-picture techniques, to study the initial accumulation of PrP aggregates in axons. The researchers observed that mutant PrP produced in the soma is enclosed in vesicles that get moved into the axon along railways called microtubules.

The researchers observed that this movement pushes much of the PrP far out into axons, where PrP-containing vesicles gather and merge. Mutant PrP forms large aggregates—which Sandra Encalada, PhD, the Arlene and Arnold Goldstein associate professor in the department of molecular medicine at Scripps Research and study senior author calls endoggresomes—that axons cannot dispose.

“We’re hopeful that these findings will lead to a better understanding of prion and other neurodegenerative diseases, as well as new strategies for treating them,” explained  Encalada.

The researchers also discovered a complex of key proteins as being responsible for steering PrP into axons and causing aggregation associated with large axonal swellings.

The findings give hope that protein-aggregate diseases of the brain, may be prevented or treated by interrupting the trafficking process that brings vesicle-encapsulated, aggregate-prone proteins out into axons.

These findings may lead to the development of new therapeutics for prion diseases and other neurodegenerative diseases.