Introduction to Prions:
When a misfolded prion enters a healthy organism, it causes already-existing, correctly folded proteins to transform into the form of a misfolded prion. Therefore, other normal proteins misfold into prion form using prions as a template. Prion disorders, also known as transmissible spongiform encephalopathies, are a class of neurodegenerative illnesses that are always fatal and are typified by motor impairment and progressive dementia.
Animal diseases include Scrapie in sheep, Bovine Spongiform Encephalopathy (BSE or “mad cow disease”) in cattle, and Kuru, Creutzfeldt-Jakob disease (CJD), and Fatal Familial Insomnia (FFI) in humans have all been linked to prions.
Structure and Function of Normal Prion Protein (PrPC):
The native version of the prion protein, called PrPc (Prion Protein Cellular), is mostly found in the neurons of healthy animals, particularly in the brain, and is encoded by the gene Prnp, which stands for “Prion-protein.”
PrPC is a cell-surface glycoprotein that is linked to glycosylphosphatidylinositol. PrPC may play a part in copper transport or metabolism since its N-terminal region contains a sequence that has a high-affinity binding site for copper ions. Since scrapie in sheep was the first prion illness to be identified, the pathogenic form of the prion protein is known as PrPSc (prion protein Scrapie). PrPSc shares the same amino acid sequence as PrPC from the same species but has a different shape.
Pathogenic Prion Protein (PrPSc)- Misfolding and Transmission:
Instead of subverting host enzymes or genes like a virus does, a pathogenic prion “replicates” by transforming native prion proteins that are already present in the host cell into the pathogenic form when it enters a host cell that is expressing native prion protein. As the pathogenic prions build up, they create insoluble aggregates in the neural cells that cause disease symptoms that are always neurological and are typically caused by the destruction of the brain or other nerve tissue.
Pathogenesis of prion diseases:
The buildup of aberrant PrP isoforms, which depends on the transformation of normal PrP into PrPSc, is the cause of prion disorders. This transformation is a conformational shift in PrP from a primarily alpha-helical to a predominantly beta-sheet form rather than a chemical alteration. Long strands of polymerized proteins or amyloid fibrils that resemble crystals are assembled as a result of the initial PrPSc molecule appearing spontaneously and converting other PrP molecules to PrPSc.
Prion disease susceptibility is mostly determined by the polymorphism (valine or methionine) at codon 129 in PrP. This polymorphism also affects the illness’s incubation period and clinical characteristics.
It has been demonstrated that pathogenic prion membrane attachment is required for the onset of illness symptoms, and PrPC operates in the cell as a cytoplasmic membrane glycoprotein. One prominent aspect of prion disease is neuronal loss, and apoptosis is the mechanism by which cells die in prion disease. When PrPSc is expressed on neural cells, microglial cells become activated and release reactive oxygen species and pro-inflammatory cytokines. Neuronal cell death may result from a lack of PrPC function in addition to the direct and indirect harmful effects of PrPSc. Disturbances in brain copper metabolism and antioxidative defense mechanisms are examples of potential pathways.
Human diseases of Prions:
Kuru
Prion disease, Kuru results in psychological and neurological manifestations. The preclinical or asymptomatic phase, also called the incubation period, lasts between possibly 5 to 20 years following initial exposure and the clinical stage lasts an average of 12 months.
The symptoms of Kuru are decreased muscle control, tremors, deterioration of speech, and dysarthria (slurred speech) progressing to incapability of walking without support and suffers ataxia (loss of muscle coordination) and severe tremors, emotional unstablity, severe ataxia, dysphagia, unresponsiveness to his or her surroundings, and acquires ulcerations. An infected person usually dies within three Months to two years after the first symptoms
Creutzfeldt–Jakob disease or CJD
Creutzfeldt-Jakob disease (CJD) is always fatal and incurable, causing the brain tissue to degenerate rapidly, and as the disease destroys the brain, the brain develops holes and the texture changes to resemble that of a sponge.
CJD are thought to be caused by the consumption of food contaminated with prions, which also cause BSE-Bovine Spongiform Encephalopathy and contamination with tissue from an infected person, usually as the result of a medical procedure that include blood transfusion from the infected person, use of human-derived pituitary growth hormones, gonadotropin hormone therapy, corneal and/or meningeal transplants.
Rapidly progressing dementia, memory loss, personality changes, hallucinations, anxiety, sadness, paranoia, obsessive-compulsive behaviors, and psychosis are all signs of CJD.
Physical issues including speech impairment, jerky movements (myoclonus), balance and coordination issues (ataxia), altered gait, stiff posture, and seizures accompany this. The majority of victims pass within six months after the onset of symptoms, frequently from pneumonia brought on by compromised coughing reflexes. Some patients have been known to live for four to five years with primarily psychological symptoms until the illness worsens and causes more physical symptoms, which usually result in a diagnosis and an unavoidable death within the first year of diagnosis.
Fatal familial insomnia (FFI)
Fatal familial insomnia (FFI) is a rare autosomal dominant inherited prion disease of the brain. It is almost always caused by a mutation in the PRNP gene, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia (sFI). FFI has no known cure and involves progressively worsening insomnia, which leads to hallucinations, delirium, and confusional states like that of dementia that worsens over time, elevated blood pressure, episodes of hyperventilation, excessive tearing, sexual and/or urinary tract dysfunction, jerky eye movements, dysarthria. Ultimately, FFI is fatal within a few months to a few years after the development of symptoms.
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