University years

What is a prion?

After the last few posts about my Neurobiology Master’s thesis, today I would like to follow up on the story of how I ended up doing a PhD in Germany and I will write about the first semester of my second and last year of Master’s.

After that pretty hard first year, where I realized that Physics was very important for Neurobiology and that electrophysiology and recordings were definitely not my piece of cake, I finally got fascinated by the “Neurogenetics and Neuropathology” classes and I was not just studying to pass the finals, but I was eventually interested and stimulated to look up topics and go deeper into the different subjects. Obviously, since I started working on my Master’s project already during the second semester of the first year (as I have already mention here), the time left in between the different classes (such as “Neuroimmunology” or “Advanced Systemic Neurophisiology”) and having friends and a life outside the University was mot that much. However, and I can not stress this enough, as long as you have an interest, even the 15 minutes in between classes can be used to learn something new or get lost in your passion.

And this is exactly how passionate I was about this “Neurogenetics and Neuropathology”. This course started by talking about the genetic basis of several major neurological and psychiatric disorders, allowing us to realise the importance of the genetic determinant in the development and function of the central nervous system. Moreover, we started analyzing those disorders for which it is assumed an ever greater contribution by the individual’s genetic abnormalities, such as autism, attention deficit or hyperactivity, anxiety and depression, schizophrenia and the aggressiveness. The course was eventually wrapping up with classic neuropathologies (such as Alzheimer’s, Parkinson’s, ALS) as well as those emerging in clear penetrance family such as prion diseases (transmissible spongiform encephalopathies).

Indeed, today for the SRF I will talk about prions, an infectious agent that consists primarily of a protein found in the membranes of normal cells, but in this case the protein has an altered shape, generating great interest in what seems to be a totally new kind of mechanism of disease.

“Science Related Fact” (SRF):

As I have already anticipated above, a prion is a type of protein that can trigger normal proteins in the brain to fold abnormally. The term prion was first used to describe the mysterious infectious agent responsible for several neurodegenerative diseases found in mammals, including Creutzfeldt-Jakob disease (CJD) in humans. Contrary to previously known pathogens, such as bacteria and viruses, that contain nucleic acids, which enable them to reproduce and spread, the prion, the infectious agent causing these neurodegenerative diseases consists only of protein, with no nucleic acid genome, an initially heretical hypothesis.

This hypothesis explained why the mysterious infectious agent is resistant to ultraviolet radiation, which breaks down nucleic acids, but is susceptible to substances that disrupt proteins. Indeed, it is believed that the distorted protein could bind to other proteins of the same type and induce them to change their conformation as well, producing a chain reaction that propagates the disease and generates new infectious material. Since then, the gene for this protein has been successfully cloned and studies using transgenic mice have supported the prion hypothesis. The evidence in support of the hypothesis is now very strong, though not incontrovertible.

In people, prions impair brain function, causing changes in memory, personality and behavior; a decline in intellectual function (dementia); and abnormal movements, particularly ataxia (that is difficulty with coordinating movements). The signs and symptoms of prion disease typically begin in adulthood and worsen with time, leading to death within a few months to several years.

Between 10 and 15 percent of all cases of prion disease are caused by mutations in the PRNP gene. Since these mutations can run in families, these forms of prion disease are classified as familial. The PRNP gene provides instructions for making a protein called prion protein (PrP). Although the precise function of this protein is still unknown, researchers have proposed roles in several important processes (such as the transport of copper into cells, protection of neurons from injury and communication between neurons). In familial forms of prion disease, PRNP gene mutations result in the production of an abnormally shaped protein, known as PrPSc. In a process that is not fully understood, PrPSc can attach to the normal protein (PrPC) and promote its transformation into PrPSc. The abnormal protein builds up in the brain, forming clumps that damage or destroy neurons (see schematic below). The loss of these cells creates microscopic sponge-like hole in the brain, which leads to the signs and symptoms of prion disease.

Schematic of the prion disease development. From “Antisense oligonucleotides extend survival of prion-infected mice” by Raimond et al., 2019 DOI:10.1172/jci.insight.131175

The other 85 to 90 percent of cases of prion disease are classified as either sporadic or acquired. Sporadic disease occurs when PrPC spontaneously and for unknown reasons is transformed into PrPSc. On the other hans, acquired prion disease results from exposure to PrPSc from an outside source. For example, variant CJD (vCJD) is a type of acquired prion disease in humans that results from eating beef products containing PrPSc from cattle with prion disease.

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