The Prion Paradox: Exploring the Neurodegeneration of CJD

Alfons Maria Jakob - one of the neuropathologists whose work led to the discovery of CJD

Introduction

Creutzfeldt-Jakob disease. One of the most unique and rare neurological disorders discovered in recent years. Considered to be the human “Mad Cow Disease,” this illness is characterized by an inability to properly fold proteins in the brain (also referred to as a prion disease). As a result, the brain experiences a rapid loss of gray matter tissue, causing abnormalities in speech patterns, cognitive functioning, memory, motor control, and overall behavior. In this article, we will discuss what CJD is, its overall effect on neural structure, and its social significance.

Visualization of a control brain and the brain of an individual with CJD. Notice the decreased grey matter, which are the cell bodies of neurons (Heo et al., 2024)

What is CJD?

Due to the rarity of CJD and its widespread effects on cognitive functioning, it is especially challenging for clinicians to accurately identify the source of an individual's symptoms. A 70-year-old patient who was experiencing difficulty sleeping, irritability, forgetfulness, and motor control was diagnosed with Alzheimer’s-type dementia. However, he later returned with vivid delusions and his speech became intelligible, ultimately forcing him to remain hospitalized. Months passed before tests revealed unresponsive 14-3-3 proteins (the most direct indicator of CJD), and the patient was finally diagnosed correctly (Gozke et. al, 2008).

CJD is a prion disease. Prion diseases arise from the abnormal folding of a protein (the prion protein), which is mainly found in the brain. In our case, the development and progression of CJD occur when a normal cellular prion protein (PrPC) spontaneously undergoes conversion into a misfolded protein (PrPSc). The abnormal folding of one protein catalyzes the formation of more and more PrPSc, with each serving as a template for the next. This is the suspected biological basis for CJD (Imran and Mahmood, 2011). 

Neuroscience of CJD

So, we now know (very vaguely) how CJD starts, but how does it cause the symptoms that our 70-year-old patient described? One answer can be found by looking at the kind of illness that CJD is categorized as, which is a transmissible spongiform encephalopathy (TSE). CJD gives rise to multiple tiny holes throughout the brain, making the brain appear sponge-like (hence the word, spongiform). These lesions (brought about by the misfolding of proteins) give rise to the disabling symptoms that come with CJD, such as memory problems, confusion, and severe mental, as well as physical, impairments. 

On top of this, our body’s inflammatory response also plays a role in the neuropathology of CJD. Usually, our inflammatory response is triggered by foreign substances that our body detects in our bloodstream, such as viruses. However, in patients with CJD, the buildup of prion deposition can actually trigger this response in the brain. A 2002 study showed that in the cerebrospinal fluid of patients with CJD, there were significant increases in microglia, astrocytes, and the protein IL-1β compared to controls. Microglia are the resident immune cells in our brain, and astrocytes are star-shaped glial cells that are essential for maintaining neural function. IL-1β is a pro-inflammatory signaling molecule (called a cytokine) that serves as the central mediator of inflammation. Altogether, the upregulation of these three entities suggests an increased inflammatory state in patients with CJD. Specifically, these results indicate that the immune system may be “attacking” the brain, helping to facilitate neurodegeneration and neuronal death. (Van Everbroeck et al., 2002).

Social Significance

CJD seems to be an illness that is incredibly far removed, especially since most of the people reading this article are healthy young college students. On top of that, it only affects one in every one million people, primarily elderly individuals. The most striking aspect of this illness however is how random it is; there are no direct correlations or risk factors. Furthermore, all cases are fatal. Our current pharmacology cannot counter CJD’s symptoms, and the rarity of this disorder restricts the development of future treatments.  

We don’t mean to scare you with all of this, saying how this disease can impact anybody at any given time with no specific reason. Sure, the chances of you developing CJD are extremely rare, but that doesn’t mean that we should ignore it because it’s not happening to us. A progressive disease such as this is just one example of how some things are amazingly out of our control. The fact that the disease exists and causes immense hardship is a call for all of us to learn how to appreciate life and all of its uncertainties because there is truly no knowing what could happen. 

Live for now, all the time.

Sources

Gozke, E., Erdal, N. & Unal, M. (2008). Creutzfeldt-Jacob Disease: a case report. Cases Journal 1, 146 (2008). https://doi.org/10.1186/1757-1626-1-146 

Heo, H., Park, H. Y., Suh, C. H., Shim, W. H., Lim, J., Lee, J., & Kim, S. J. (2024). Development of statistical auto-segmentation method for diffusion restriction gray matter lesions in patients with newly diagnosed sporadic Creutzfeldt–Jakob disease. Scientific Reports, 14(1), 1-11. https://doi.org/10.1038/s41598-024-51927-6 

Imran, M., Mahmood, S. (2011). An overview of human prion diseases. Virol J 8, 559 https://doi.org/10.1186/1743-422X-8-559 

Van Everbroeck, B., Dewulf, E., Pals, P., Lübke, U., Martin, J., & Cras, P. (2002). The role of cytokines, astrocytes, microglia and apoptosis in Creutzfeldt-Jakob disease. Neurobiology of Aging, 23(1), 59-64. https://doi.org/10.1016/S0197-4580(01)00236-6