Prions beget prions, we know, but we lack a good understanding of prion diseases. We can follow the progress of prion diseases up to a certain point—the accumulation of misfolded proteins. To press forward, we need to see exactly how prions cause neuronal degeneration, the proximate cause of the symptoms associated with prion disorders, symptoms such as rapidly progressive dementia, seizures, and personality changes.
In humans, prion disorders include Creutzfeldt-Jakob disease and kuru; in cows, bovine spongiform encephalopathy, or “mad cow disease.” To better understand how prions cause nerve damage in these disorders, scientists based at Boston University School of Medicine applied a method they previously described for culturing nerve cells from the hippocampal region of the brain. By exposing their cultured nerve cells to prions, the scientists, led by David A. Harris, M.D. Ph.D., professor, chair of biochemistry at Boston University School of Medicine, hoped to reveal the molecular pathways that prions follow to cause synaptotoxicity.
In earlier work, the scientists showed that neurons exposed to a purified prion, PrPSc showed rapid retraction of dendritic spines. In a new study (“Prions activate a p38 MAPK synaptotoxic signaling pathway”) that appeared recently in the journal PLOS Pathogens, the scientists pharmacologically dissected the underlying cellular and molecular mechanisms.
“We show that PrPSc initiates a stepwise synaptotoxic signaling cascade that includes activation of NMDA receptors, calcium influx, stimulation of p38 MAPK and several downstream kinases, and collapse of the actin cytoskeleton within dendritic spines,” the article’s authors wrote. “Pharmacological inhibition of any one of the steps in the signaling cascade, as well as expression of a dominant-negative form of p38 MAPK, block PrPSc-induced spine degeneration.”
Essentially, the scientists defined a stepwise molecular pathway underlying prion synaptic toxicity, which involves activation of glutamate neurotransmitter receptors, influx of calcium ions into the neuron, and stimulation of specific mitogen-activated protein kinases, which attach phosphate groups to proteins to regulate their activity. In addition, the scientists demonstrated that specific drugs, as well as a dominant-negative kinase mutant, block these steps and thereby prevent the synaptic degeneration produced by prions.
Specifically, the Boston University team found that inhibition of p38 MAPKα (an enzyme that typically responds to stress, such as ultraviolet radiation and heat shock) prevented injury to nerve connections and promoted recovery from the initial damage. Hippocampal nerve cells that had a mutation preventing normal function of p38 MAPKα were also protected, seeming to confirm the role the enzyme plays in this disease process.
“Our results provide new insights into the pathogenesis of prion diseases,” says Dr. Harris. “They uncover new drug targets for treating these diseases, and they allow us to compare prion diseases to other, more common neurodegenerative disorders like Alzheimer's disease.”