PRNP - prion protein (Kanno blood group) |Elisa - Clia - Antibody - Protein

Background

The PRNP gene, encoding the prion protein (PrP), plays a critical role in both neurobiology and disease. This gene is located on chromosome 20 in humans and encodes the cellular prion protein, PrP^C. Prion proteins are unique in their ability to exist in multiple conformations, including a pathological form, PrP^Sc, associated with prion diseases. Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are neurodegenerative disorders marked by rapidly progressive neuronal loss and a spongiform appearance in brain tissue. TSEs include diseases such as Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gerstmann-Sträussler-Scheinker syndrome (GSS), and kuru.

The prion protein (PrP) is primarily expressed in the central nervous system (CNS), especially in neurons, but it is also found in other tissues. While the physiological function of PrP^C remains partially understood, it is thought to be involved in cellular processes like cell signaling, protection against oxidative stress, and synaptic function. Its pathological form, PrP^Sc, is formed by a misfolded conformation of PrP^C that becomes self-propagating, causing other normal PrP^C molecules to misfold. This cascade leads to the accumulation of toxic aggregates and extensive neuronal damage, a hallmark of prion diseases.

Protein Structure

The prion protein (PrP) is a glycoprotein with a highly flexible structure, and it can undergo significant conformational changes under specific conditions:

Primary Structure:

• Human PrP consists of 253 amino acids and has a highly conserved sequence across species, highlighting its functional importance. The sequence includes a signal peptide at the N-terminus and a glycosylphosphatidylinositol (GPI) anchor at the C-terminus, which helps anchor the protein to the cell membrane.
• It contains two N-linked glycosylation sites (Asn181 and Asn197 in humans), which are important for the stability and trafficking of the protein.

Secondary and Tertiary Structure:

• PrP has a highly flexible N-terminal region (amino acids 23-120) and a structured C-terminal region (amino acids 121-231).
• The C-terminal domain consists mainly of three α-helices (H1, H2, and H3) and two short β-strands (S1 and S2), which are connected by loops. The α-helix H3 is longer and forms the core of the protein’s helical structure.
• The structured C-terminal domain of PrP^C is stabilized by a disulfide bond between two conserved cysteine residues (Cys179 and Cys214), which is essential for maintaining its proper folding and functional stability.

Quaternary Structure and Aggregation:

• While PrP^C is monomeric and soluble, the pathological PrP^Sc form is aggregated and insoluble. In PrP^Sc, the structure shifts to contain a higher β-sheet content, leading to the formation of amyloid fibrils. These fibrils are resistant to proteolytic degradation and accumulate within neuronal tissue, causing cellular toxicity.

GPI Anchor:

• The GPI anchor at the C-terminus attaches PrP^C to the outer surface of the cell membrane, where it interacts with other membrane proteins and participates in cellular processes. The anchor is essential for PrP^C’s localization, but in the pathological state, PrP^Sc aggregates can dissociate from the membrane and spread through the extracellular space.

Classification and Subtypes

Prion proteins exist in two major conformational subtypes:

PrP^C (Cellular prion protein):

• PrP^C is the normal, non-pathogenic conformation of the prion protein. It is primarily composed of α-helices and is soluble, glycosylated, and sensitive to proteolysis. This conformation is essential for the normal physiological functions of PrP.

PrP^Sc (Scrapie prion protein):

• PrP^Sc is the pathological, misfolded form that is highly resistant to proteolysis and has a high β-sheet content. PrP^Sc is infectious and can induce the misfolding of PrP^C into PrP^Sc, propagating the disease. This misfolded form is found in prion diseases and is responsible for the neurotoxicity and neurodegeneration seen in these disorders.

Function and Biological Significance

The normal functions of PrP^C are not fully understood, but it appears to play roles in:

Cell Signaling and Neuroprotection:

• PrP^C is involved in cell signaling pathways, especially those related to cell survival and neuroprotection. It can bind to several proteins and metal ions, including copper, and may have roles in oxidative stress regulation. By binding copper, PrP^C can influence cellular antioxidant responses and help protect neurons from oxidative damage.

Synaptic Function and Plasticity:

• PrP^C is localized on the cell membrane near synapses, suggesting it plays a role in synaptic function. It has been shown to participate in synaptic plasticity, which is crucial for learning and memory. Loss of PrP^C function may impair synaptic function, potentially contributing to cognitive deficits.

Regulation of Cell Adhesion and Migration:

• PrP^C has been implicated in cell adhesion processes by interacting with proteins in the extracellular matrix, potentially influencing cell migration. This role may be relevant in both neuronal development and immune system function.

Cellular Prion Propagation:

• While PrP^C itself is not infectious, it is essential in the propagation of prion diseases. When PrP^C comes into contact with the misfolded PrP^Sc, it can adopt the pathological conformation, leading to a cascade of PrP^Sc formation and the spread of prion disease within the CNS.

Clinical Issues

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases caused by the conversion of PrP^C into PrP^Sc. These diseases can be sporadic, inherited, or acquired through infectious transmission. Some notable clinical issues include:

Creutzfeldt-Jakob Disease (CJD):

• CJD is the most common human prion disease, characterized by rapid cognitive decline, motor symptoms, and cortical degeneration. It has several subtypes: sporadic, familial (linked to mutations in the PRNP gene), and iatrogenic, which can result from exposure to prion-contaminated surgical instruments or tissue transplants.

Variant Creutzfeldt-Jakob Disease (vCJD):

• vCJD is associated with consuming beef products contaminated with bovine spongiform encephalopathy (BSE), also known as “mad cow disease.” vCJD has a distinct clinical and pathological profile compared to sporadic CJD and has raised concerns about prion transmission through the food supply.

Fatal Familial Insomnia (FFI):

• FFI is an autosomal dominant prion disease caused by a mutation in the PRNP gene. It primarily affects the thalamus, leading to sleep disturbances, severe insomnia, and autonomic dysfunction.

Gerstmann-Sträussler-Scheinker Syndrome (GSS):

• GSS is another genetic prion disease caused by mutations in PRNP. It presents with progressive cerebellar ataxia, dementia, and other motor symptoms.

Kuru:

• Kuru is a prion disease found in certain tribes in Papua New Guinea and is linked to ritualistic cannibalism. It is characterized by progressive tremors, loss of coordination, and ultimately, death.

Prion diseases are universally fatal and currently lack effective treatments. Research is ongoing to develop therapeutic strategies to prevent PrP^C misfolding or to clear PrP^Sc from affected tissues.

Summary

The PRNP gene encodes the prion protein (PrP), a cell-surface glycoprotein primarily expressed in the CNS. PrP can exist in two main forms: the normal, non-infectious PrP^C and the misfolded, infectious PrP^Sc. Structurally, PrP^C consists of a flexible N-terminal domain and a structured C-terminal domain with α-helices, stabilized by disulfide bonds and anchored to the cell membrane via a GPI anchor. The misfolded PrP^Sc form, characterized by a high β-sheet content, can convert PrP^C into PrP^Sc, propagating prion diseases.

PrP^C plays roles in cell signaling, synaptic function, neuroprotection, and cellular adhesion. However, in prion diseases such as CJD, FFI, and GSS, PrP misfolding leads to neurodegeneration and a spongiform appearance in the brain. Despite extensive research, prion diseases remain fatal, with no effective treatments currently available. The study of PRNP and PrP^C/PrP^Sc dynamics continues to be an area of intense scientific focus due to its implications in neurodegenerative disease mechanisms and therapeutic potential.