Study Identifies Potential Treatment Target for Prion Diseases
A new study by Researchers from Boston University School of Medicine has identified a molecular pathway that may explain the exact mechanism of damage to the neuronal connections in the brain and spinal cord in patients with prion diseases, opening the door to new treatment targets. Prion diseases are a group of rapidly fatal neurological disorders that include Creutzfeldt-Jakob disease and kuru in humans and bovine spongiform encephalopathy (“mad cow disease”) in cattle. These diseases are caused by the spread of prions in the brain, which are an altered form of a normal, cellular protein. As these abnormal proteins interact with normal proteins in the brain, they promote misfolding, leading to rapidly progressive dementia, seizures, and other neurologic effects.
The researchers cultured nerve cells from the hippocampal region of the brain and then exposed them to prions to cause damage to nerve cell connections, as occurs with prion diseases. They then added various chemical compounds with known inhibitory effects on cellular responses to stressful stimuli to see if they could identify the pathways involved.
They found that inhibition of p38 MAPK prevented injury to nerve connections and reversed the degenerative process that had already begun. Hippocampal nerve cells that had a mutation preventing normal function of p38 MAPK were also protected, lending further evidence that enzymes play a key role in this disease process.
The investigators concluded, “Taken together, our results provide powerful insights into the biology of prion neurotoxicity, they identify new, druggable therapeutic targets, and they allow comparison of prion synaptotoxic pathways with those involved in other neurodegenerative diseases.”
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Fang C, Wu B, Le NTT, et al. Prions activate a p38 MAPK synaptotoxic signaling pathway. PLOS Pathogens. 2018;14(9):e1007283.