Sandra Encalada, PhD, of Scripps Research, was awarded $4.1 million from the National Institute on Aging, part of the National Institutes of Health (NIH), for research into how prion diseases kill brain cells. Some prion diseases, such as Creutzfeldt-Jakob disease (CJD), can arise sporadically or from an inherited mutation in the prion protein. In other cases, prion diseases can be transmissible between animals or—in even more rare instances—infect people who eat contaminated meat. Whatever the underlying cause, prion diseases lead to dementia and eventually death, as misfolded prion proteins spread through the brain, killing neurons.
“There is a lot of importance to understanding prion diseases even though they are relatively rare,” says Encalada, who is the Arlene and Arnold Goldstein Associate Professor of Molecular Medicine. “We’re very excited that this grant will allow us the opportunity to build off our previous work to not only lead to treatments for prion diseases, but to a better understanding of other neurodegenerative diseases that progress through the brain in similar ways.”
Neurons in the brain typically have central cell bodies with a long tentacle-like protrusion called the axon. Researchers know that axons—which are responsible for transmitting signals to neighboring cells—are especially vulnerable to neurodegeneration. In prion diseases, an early sign that a cell is affected is the development of characteristic clumps of swelling along the axon, like beads along a string.
“A big question in the field has been what is so different about the axon than the rest of the neuron that makes this happen, and how can we stop it,” says Encalada.
Last year, in studies using isolated mouse brain cells, her team made new headway into answering this question. They discovered key molecular pathways that move misfolded prion proteins into the axons of cells. They also showed that normal cellular waste disposal mechanisms were less effective in the axons, and so the prions accumulated into toxic masses dubbed “endoggresomes.”
With the new grant, Encalada and her colleagues plan to continue testing the relevance of these molecular pathways to various forms of prion diseases. They will move from studies in isolated cells to mice with inherited mutations in the prion protein that make them prone to disease. In a collaboration with Christina Sigurdson, DVM, PhD, of UC San Diego, they will also probe whether infectious prion diseases—such as scrapie, which affects sheep—impact the axons of cells in the same ways. And with Uri Manor, PhD, of the Salk Institute, they will use high-resolution microscopy to assemble more detailed pictures of the three-dimensional structure of endoggresomes.
“Understanding these very basic pathways can shed a lot of light on how we can target misfolded prion proteins with therapeutics,” says Encalada.
She also points out that, although other neurodegenerative diseases don’t directly involve the misfolding of prion proteins, the same defects in clearing molecular waste and aggregates from brain cells may contribute to diseases including Alzheimer’s, Parkinson’s and Huntington’s diseases.
This article is based on a press release from the Scripps Research Institute.