By Michael Howell
A recent study by scientists at Rocky Mountain Laboratory in Hamilton yielded some surprising results that shed light on the early development and spread of prion diseases in the brain. Prion diseases are degenerative neurological diseases that involve a “misfolded protein,” known as a prion. The prion replicates itself by causing other normal proteins to misfold and, in a process called “seeding,” it spreads abnormal proteins throughout the brain like an infection.
Bovine spongiform encephalopathy (Mad Cow Disease) in cattle; chronic wasting disease in deer and elk; scrapies in sheep and variant Creutzfeldt-Jakob disease in humans are all prion diseases, but the one under study at the lab was a form of scrapies that was developed in laboratory mice about fifty years ago.
According to Dr. Bruce Chesebro, Chief Scientist at the Laboratory of Persistent Diseases at RML and lead author of the article, understanding how this prion disease spreads through the brain could lead to the development of way to block it. And what is learned here could potentially be applied to other diseases. The article was published September 22 in Microbial Biofilms, an open access journal published by the American Society for Microbiology. [Chesebro B, Striebel J, Rangel A, Phillips K, Hughson A, Caughey B, Race B. 2015. Early generation of new PrPSc on blood vessels after brain microinjection of scrapie in mice. mBio 6(5):e01419-15. doi:10.1128/mBio.01419-15.]
Protein misfolding and aggregation in the central nervous system appear to be key to the pathogenesis and progression of several neurodegenerative diseases of humans besides prion disease, including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis.
According to the article, in all of these diseases, an aggregated misfolded host protein appears to accumulate progressively in certain regions of the nervous system, resulting in a fatal outcome after a clinical phase usually lasting years. The specific host protein(s) involved in each of these diseases is different. However, the mechanisms of generation appear to be similar, as all involve this “seeding” process.
Chesebro said the common test for the presence of prions in experimental mice is to crush the entire brain and mix it into a certain gel. When an electric current is be passed across it, the proteins migrate and are separated out in order of size.
This method confirms the presence of an infection, but it you would have to take hundreds and hundreds of cross section slides of the mouse brain to find the exact location of an infection. “It would be like looking for a needle in a haystack,” said Chesebro.
Interestingly enough, it was actually the very precise use of a needle that brought the answer to light.
Chesebro and his team , using the latest technology, developed a method of delivering an inoculation into the brain of a mouse with exact placement in the brain every time. This greatly increased the chances of getting a good microscopic picture of the infection. In their experiment, signs of prion production were detected within 30 minutes of inoculation. Prion accumulation was detected as early as three days following injection and again at seven days using a couple of assay methods.
The main site of new generation turned out to be on the outside of small and medium blood vessels. This was a new and surprising discovery. According to Dr. Chesebro, this location suggested that structural components of the blood vessel basement membrane or perivascular astrocytes might act as cofactors in the initial generation of this particular prion protein. It also implies a role for the brain interstitial fluid drainage in the early infection process.
A new test (RTQC) was also utilized that is so sensitive that it can detect the results of the inoculation. One thing learned from this is that the body appears to be able to combat the disease and a study of that immune system response could lead to a treatment.
“We know mice can destroy the abnormal protein,” said Chesebro, “In this mouse it’s there within thirty minutes, but it goes away within three days.” He said the same thing has been discovered about some forms of cancer, and drugs designed on the basis of the body’s natural immune system response have been able to successfully disrupt the spread.
“It’s a battle between the immune system and the prions,” said Chesebro, “But we can try to influence the outcome with drugs. There is hope.” He said there is not only hope for the one out of a million people who come down with Variant CJD, a pretty rare disease, but hope for the many people who are or may someday be suffering from Alzheimer’s and Parkinson’s and other prion diseases.
But, like the disease that they are looking to combat, the research, too, is a slow moving process and it may be a long time before these laboratory efforts yield something like a cure.
“There is progress, though,” said Chesebro. He said even if it’s hard for the average person to understand the significance of the study, given the complex scientific nomenclature involved, it is exciting news to experts. It is a big step towards what could be a cure for one or more diseases that, today, remain incurable and inevitably fatal.
Ed Gehrman says
The main reason it has been almost impossible
to understand TSE and all the so-called “prion” diseases is the mistaken idea that prions are the cause. Dr. Frank Bastian has shown that TSE are the result of infection by Spiroplasma and the prions show up after the infection has already begun. Read Dr.Bastian’s eye opening research at tseresearchcenter.org.
Ed