Wasting Disease, Chronic

Prions are the abnormal, pathogenic agents that are transmissible and are able to induce abnormal folding of specific normal cellular proteins. Prion disease is an umbrella term for a group of fatal and currently untreatable neurodegenerative diseases that not only affect humans, but also wild and captive animals. These diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, or 'mad cow disease'), and chronic wasting disease (CWD) affecting deer, elk and moose. Prions are the abnormal, pathogenic agents that are transmissible and are able to induce abnormal folding of specific normal cellular proteins.Prion disease is an umbrella term for a group of fatal and currently untreatable neurodegenerative diseases that not only affect humans, but also wild and captive animals. These diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, or "mad cow disease"), and chronic wasting disease (CWD) affecting deer, elk and moose. The central event in these diseases is the conversion of the prion protein (PrPC) from its normal shape into a pathological structure (PrPSc) that is toxic to neurons and can replicate itself through binding to unconverted PrPC molecules. This ability to self-replicate makes these misfolded proteins infectious, which has enormous implications for public health. In a new study, researchers from Boston University Chobanian & Avedisian School of Medicine have identified 10 compounds that are able to reduce PrPSc levels in infected cells and have shown that the most potent molecules can also prevent the toxicity that was observed when applying PrPSc to cultured neurons. "Excitingly, five of these molecules have a history of use in humans: rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and SA 4503 and ANAVEX2-73, which are in clinical trials for ischemic stroke and Alzheimer's disease, respectively," explained lead author Robert C.C. Mercer, PhD, an instructor of biochemistry and cell biology at the school. The researchers had initially explored the anti-prion properties of these molecules because they were known to bind to the sigma receptors (σ1R and σ2R), which they had reason to believe were involved in prion proliferation. Using gene knockout technology (CRISPR), they determined that the sigma receptors were not the relevant targets of these drugs, from the perspective of their anti-prion properties. Using Neuro2a cells (N2a) from an experimental model that had been infected with prions, these cells were then exposed to increasing concentrations of each drug, and the levels of PrPSc were determined. They then used CRISPR technology to "edit" the σ1R and σ2R genes, such that they no longer coded for a protein, and found this had no effect upon the decrease in PrPSc levels they observed when applying the drugs. This led them to conclude that σ1R and σ2R were not responsible for the anti-prion effects of these drugs. They then went on to test the ability of these drugs to inhibit the PrPC to PrPSc conversion and found they had no effect on these cell-free reactions, indicating that another protein mediates the effects of these drugs. According to the researchers, prion diseases have enormous public health implications from the safety of the blood supply to the proper decontamination of surgical tools used in neurosurgery. "From a clinical standpoint, we believe this research has uncovered anti-prion properties of drugs that have already been shown to be safe to use in humans. Because of this, especially considering the absence of any effective treatment for these diseases, these compounds could be re-purposed for treatment of prion diseases," said corresponding author David A. Harris, MD, PhD, the Edgar Minas Housepian professor and chair of biochemistry & cell biology at the school. These findings appear online in the journal ACS Chemical Neuroscience. Funding for this study was provided by the National Institutes of Health grant number 5R01NS065244, awarded to David A. Harris. Robert C.C. Mercer is supported by grants from the Department of Defense (W81XWH-21-1-0141) and the Creutzfeldt-Jakob Disease Foundation.

FRIDAY, July 14, 2023 -- Ticks may be responsible for the spread of chronic wasting disease (CWD) in Wisconsin’s deer population, according to a new study. Researchers at the University of Wisconsin-Madison have found that ticks can harbor transmissible amounts of the protein particle that causes CWD, a fatal neurological disease seen in deer, elk and moose. The pathogen, prion, can pass through soil or through bodily fluids, including feces. Prion can prompt certain proteins to fold abnormally, particularly in the brain. That can prevent these proteins from carrying out their normal functions. Over time, the CWD prion can cause severe brain damage and eventually death in deer, the study explained. While a lot of CWD studies focus on the role of soil in the disease’s spread, researcher Heather Inzalaco was curious about other means of transmission. She's a researcher in the Wisconsin Cooperative Wildlife Research Unit, housed in the UW–Madison department of forest and wildlife ecology. “Deer live these secret lives; we don't see everything that they do,” Inzalaco said in a university news release. Inzalaco wondered if one possibility might be ticks. The arachnids acquire blood from CWD-infected deer, but she wondered if they could also host the prions. “Deer will groom one another to get places that they can't reach on their own through self-grooming,” Inzalaco said. “If they're grooming each other and they're doing that to remove ectoparasites [such as ticks], that might be problematic because they're probably eating the ectoparasites.” Inzalaco determined in the lab that ticks could carry the prions in their blood meal and that they could carry enough of the agent to infect another animal with CWD. Then she partnered with the state Department of Natural Resources to study ticks collected from deer that hunters harvested and submitted for CWD testing. Among 176 deer with ticks studied, 15 tested positive for CWD. Inzalaco determined that wild ticks also carried transmissible levels of prions, making them potential mechanical vectors for the disease. “They're just like a little CWD 'tic-tac' that are possibly being eaten by the deer,” Inzalaco said. The study did not go on further to test whether prion-carrying ticks did cause transmission to other deer. Understanding the spread can help improve management of the disease. It isn’t practical to treat all wild deer with tick preventatives, but Inzalaco believes better land stewardship could help manage tick populations. This might include having contiguous habitat of native plant communities and properly managing areas to continue a natural fire regimen. This has been shown to limit tick populations, she said. When ecosystems have a lot of invasive plants, ticks proliferate. The study findings were published online recently in the journal Nature . Sources University of Wisconsin-Madison, news release, July 7, 2023 Posted July 2023

A new study finds that ticks can harbor transmissible amounts of the protein particle that causes Chronic Wasting Disease (CWD), implicating the parasites as possible agents in the disease's spread between deer in Wisconsin. A new study from researchers at the University of Wisconsin-Madison finds that ticks can harbor transmissible amounts of the protein particle that causes Chronic Wasting Disease (CWD), implicating the parasites as possible agents in the disease's spread between deer in Wisconsin. Her findings were published in the journal Scientific reports, a Nature journal. CWD is caused by a pathogenic agent called a prion, which can pass from deer-to-deer through contact with things like prion-contaminated soil and infected bodily fluids such as urine, saliva, blood and feces. Prions, which cause disease in animals and in humans, prompt certain proteins to fold abnormally, particularly in the brain, and prevent these proteins from carrying out their normal functions. Over time, the CWD prion can cause severe brain damage and eventually death in deer. A lot of CWD studies focus on the role soil plays in spreading the fatal neurological disease among deer. But Heather Inzalaco, a researcher in the Wisconsin Cooperative Wildlife Research Unit, housed in the UW-Madison Department of Forest and Wildlife Ecology, was curious about other potential environmental and behavioral means of transmission. "Deer live these secret lives; we don't see everything that they do," Inzalaco says. She started to consider what sort of things pester deer that could be connected to CWD: Ticks were the perfect parasitic potential culprit to investigate. Ticks have a goal, of course, to feed on their host's blood. Inzalaco began to wonder if ticks that acquire blood from CWD-infected deer could also host the prions and if so, could they contain enough prions to spread the disease. The question became even more intriguing when she discovered that the most common non-aggressive social behavior that deer engage in is allogrooming. "Deer will groom one another to get places that they can't reach on their own through self-grooming," Inzalaco says. "If they're grooming each other and they're doing that to remove ectoparasites [such as ticks], that might be problematic because they're probably eating the ectoparasites." First, she needed to show that ticks can take up and harbor these prions when they feed on CWD-infected blood. She designed an experiment to do just that. "You'd think that it'd be easy to get ticks to take a blood meal, but they are surprisingly fussy in the lab," Inzalaco says. She was able to determine that ticks can not only carry the prions in their blood meal, they can also carry enough of the agent to potentially infect another animal with CWD. After seeing that the phenomenon was possible in the lab, it was time to see what was happening in the wild. Inzalaco partnered with the Department of Natural Resources to study ticks collected from deer that hunters harvested and submitted for CWD testing. Of the 176 deer with ticks she studied, 15 of the deer were also positive for CWD. Inzalaco took the ticks from the infected deer and tested the blood they contained to quantify the amount of prion the ticks harbored. She determined that these engorged, wild ticks did carry transmissible levels of prions -- just like those in the lab -- making them potential mechanical vectors for the disease. "They're just like a little CWD tic-tac that are possibly being eaten by the deer," Inzalaco says. The study did not test whether prion-carrying ticks did cause transmission to other deer. Understanding more about how CWD can spread can help improve the management of the disease. While it isn't practical to treat all wild deer with tick preventatives, Inzalaco believes better land stewardship could help manage tick populations. For instance, having contiguous habitat of native plant communities and properly managing areas to continue a natural fire regime has been shown to limit tick populations, she says, while more fragmented, unbalanced ecosystems riddled with invasive plants may allow ticks to proliferate more readily. Inzalaco says it might be possible to use ticks as a way to screen for CWD in both wild and farmed deer. Current methods of diagnosis or screening involve invasive sample collection from animals or tissue sampling after their death. While testing the ticks from deer may not lead to the same level of accuracy as testing tissue samples, it could still be a useful tool to better understanding where the disease is affecting deer population in the state. Inzalaco also believes her research can help improve the ecosystems that everyone relies on, especially the state's hunters. "We are all inextricably linked to ecosystem function and the biodiversity of those ecosystems," she says. "That is really what drives my desire to learn and do good science on a daily basis. We need to make an effort to preserve our natural heritage so that we can continue living on this planet and not be overtaken by disease and have healthy animals and healthy functioning ecosystems."