The prion protein (PrP) is a naturally occurring glycoprotein found in the brains and other tissues of mammals. It is primarily located on the surface of cells, particularly neurons in the central nervous system. This protein is encoded by the PRNP gene on chromosome 20 in humans. The term “prion” is a shortened form of “proteinaceous infectious particle,” highlighting its unique nature as an infectious agent composed solely of protein, lacking genetic material like DNA or RNA.
The Prion Protein’s Normal Role
The normal, healthy form of the prion protein, PrPC (cellular prion protein), possesses a structure rich in alpha-helices. While its precise physiological function is still being fully elucidated, research suggests its involvement in several cellular processes. PrPC plays a role in the transport of ionic copper into cells.
This protein also contributes to cell signaling pathways. It participates in the formation and maintenance of synapses, the junctions between neurons where communication occurs. PrPC has been linked to neuroprotection, helping to shield neurons from damage, and may influence cellular differentiation.
How Prion Proteins Go Rogue
The transformation of normal PrPC into its abnormal, disease-causing form, PrPSc (scrapie prion protein), is a central event in prion diseases. This conversion involves a conformational change where PrPC’s alpha-helix rich structure refolds into a form predominantly composed of beta-sheets. Misfolded PrPSc then acts as a template, inducing other healthy PrPC molecules to misfold into the abnormal conformation. This self-propagating mechanism leads to an exponential accumulation of PrPSc in brain tissue.
The abnormal PrPSc molecules are stable and resistant to degradation by cellular enzymes called proteases. As PrPSc accumulates, it forms insoluble aggregates, often referred to as amyloid plaques, within the brain. This aggregation disrupts normal cellular function, ultimately leading to damage and death of nerve cells, and the characteristic neurodegeneration seen in these diseases.
The Diseases They Cause
Misfolded prion proteins are responsible for a group of fatal neurodegenerative disorders known as Transmissible Spongiform Encephalopathies (TSEs). These diseases are characterized by the formation of tiny holes in the brain tissue, giving it a “spongy” appearance when viewed under a microscope. Human prion diseases include Creutzfeldt-Jakob Disease (CJD), which can occur sporadically, genetically, or be acquired. Other human forms are Kuru, historically linked to ritualistic cannibalism, Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI).
Animal TSEs include Bovine Spongiform Encephalopathy (BSE), commonly known as “mad cow disease,” which primarily affects cattle. Scrapie affects sheep and goats, causing neurological signs like pruritus and ataxia. Chronic Wasting Disease (CWD) impacts deer, elk, reindeer, and moose, leading to symptoms like listlessness and emaciation. These diseases typically manifest with progressive cognitive decline, personality changes, and problems with coordination.
Containing and Coping with Prion Diseases
Prion diseases can be acquired sporadically, through inherited genetic mutations in the PRNP gene, or via acquired exposure. Acquired transmission can occur through contaminated medical instruments or the consumption of infected tissues. There are currently no effective treatments or cures for prion diseases, making them invariably fatal.
Diagnosis often presents challenges due to the variability in clinical presentation and the fact that definitive confirmation frequently requires a brain biopsy performed after death. However, newer diagnostic approaches incorporating magnetic resonance imaging (MRI) and real-time quaking-induced conversion (RT-QuIC) assays are improving early detection. Public health measures focus on prevention and containment, including stringent regulations on animal feed, prohibiting the use of high-risk bovine tissues in food, and implementing robust sterilization protocols for medical instruments. Research continues to explore potential therapeutic strategies, such as the use of antisense oligonucleotides (ASOs) to reduce the production of the normal prion protein, aiming to delay or prevent disease progression, particularly in genetic forms.