Prions are unusual, disease-causing agents that can spread and cause normal cellular proteins to fold abnormally. Prion disease refers to a group of fatal neurodegenerative diseases that currently have no treatment. These diseases impact not only humans, but also wild and captive animals, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, or ‘mad cow disease’), and chronic wasting disease (CWD) in deer, elk, and moose.
Prion disease encompasses a variety of fatal neurodegenerative diseases that impact both humans and animals, such as Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, and chronic wasting disease. These diseases involve the transformation of the prion protein from its normal shape into a toxic and replicating pathological structure that harms neurons. This process affects the normal cellular proteins in the body.Tough binding to unconverted PrPC molecules is what allows these misfolded proteins to self-replicate, making them infectious and posing significant public health concerns. A recent study conducted by researchers from Boston University Chobanian & Avedisian School of Medicine has successfully identified 10 compounds that can reduce PrPSc levels in infected cells. The study also demonstrated that the most potent molecules can prevent the toxicity observed in cultured neurons when PrPSc is applied. Of particular interest is the fact that five of these molecules have a history of use in humans, including rimcazole and haloperidol for neuropsychiatric conditions.The lead author, Robert C.C. Mercer, PhD, an instructor of biochemistry and cell biology at the school, explained that they had initially studied the anti-prion properties of ions, (+)-pentazocine, SA 4503, and ANAVEX2-73 because they were in clinical trials for neuropathic pain, ischemic stroke, and Alzheimer’s disease, respectively. The researchers believed that these molecules were involved in prion proliferation as they were known to bind to the sigma receptors (σ1R and σ2R). However, using gene knockout technology (CRISPR), they determined that the sigma receptors were not the relevant targets of these drugs.
The researchers conducted an experiment to investigate the anti-prion properties of various drugs. They used Neuro2a cells (N2a) that had been infected with prions and exposed them to increasing concentrations of each drug. The levels of PrPSc were then measured. They also used CRISPR technology to disable the σ1R and σ2R genes, but found that this had no impact on the decrease in PrPSc levels when the drugs were applied. This led them to conclude that σ1R and σ2R were not responsible for the drugs’ anti-prion effects.
drugs. They then tested the drugs’ ability to stop the conversion of PrPC to PrPSc and found that they did not have any impact on these reactions happening outside of the cells. This suggests that a different protein is responsible for the effects of these drugs.
The researchers believe that prion diseases have significant implications for public health, including the safety of the blood supply and the proper decontamination of surgical tools used in neurosurgery. “From a clinical perspective, we think that this research has revealed the anti-prion properties of drugs that have already been proven to be safe for use in humans. Therefore, it is especially important to consider these findings, considering the significant impact of prion diseases.””Since there are no effective treatments for these diseases, these compounds could potentially be repurposed for prion disease treatment,” stated David A. Harris, MD, PhD, the Edgar Minas Housepian professor and chair of biochemistry & cell biology at the school, who is the corresponding author of the study. The findings have been published in the journal ACS Chemical Neuroscience. The study was funded by the National Institutes of Health grant number 5R01NS065244, awarded to David A. Harris, and Robert C.C. Mercer is supported by grants from the Department of Defense (W81XWH-21-1-0141) and the Creutzfeldt-Jakob Disease Foundation.
Â
