After an extensive series of purification procedures, scientists were astonished to find that the infectivity of the agent causing scrapie in sheep was associated with a single protein species, with no detectable associated nucleic acid. This infectious protein is designated the prion protein. It is relatively resistant to proteolytic degradation and, when infectious, tends to form insoluble aggregates of fibrils, similar to the amyloid found in other diseases of the brain.

A. Presence of prion protein in normal mammalian brain

A noninfectious form of PrP, having the same amino acid and gene sequences as the infectious agent, is present in normal mammalian brains on the surface of neurons and glial cells. It is referred to as PrP^C (cellular prion protein). Although the function of noninfectious PrP^C is unknown, it is highly conserved in nature, with the amino acid and gene sequences differing little among divergent mammalian species. Recent evidence suggests that the wild-type protein participates in signal transduction and/or metal homeostasis. The primary structure and posttranslational modifications of the normal and the infectious forms of the protein are closely related or identical. However, specific mutational changes of single amino acids at a few sites appear to be determinants of susceptibility to exogenous infection and the probability for spontaneous conversion of the nor mal PrP^C to the infectious form (PrP^Sc). The key to becoming infectious apparently lies in the three-dimensional conformation of the PrP. It has been observed that several α-helices present in noninfec tious PrP^C are replaced by β-sheets in the infectious form. Presumably, this conformational difference confers relative resistance to proteolytic degradation on infectious prions, thereby distinguishing them from normal PrP^C in infected tissue. A model for "reproduction" of the agent is shown in Figure 1.

Fig1. One proposed mechanism for “reproduction” of the infectious prion protein (PrP).

B. Epidemiology

The normal mode of transmission among animals (for example, among sheep in a flock infected with scrapie) has not been elucidated. It is clear, however, that several diseases of domestic animals have been transmitted via feed prepared from other diseased animals.

1. Bovine spongiform encephalopathy: BSE, commonly called mad cow disease, arose in British cattle presumably caused by their feed processed with animal parts prepared from diseased sheep and cattle. The obvious question raised by this occurrence is whether the BSE from infected cattle can be transmitted to humans. Although such a risk was originally considered negligible, a study of infectious material from a cluster of histologically distinctive British CJD cases in unusually young patients (now referred to as “variant,” or vCJD) indicated that animal-to-human transmission very likely did take place. Because the incubation time for symptoms to appear varies from 4 to 40 years, the likelihood of a potential epidemic caused by BSE is unknown.

 2. Kuru: An example of human-to-human transmission of a TSE is found in kuru, a disease in which the infectious agent is acquired by an individual’s exposure to diseased brain tissue in the course of ritualistic cannibalism among members of a tribe in New Guinea. Infection occurs by consuming contaminated brain tissue or via inoculation through breaks in the skin following the handling of diseased tissue. With cannibalism cessation in the late 1950s, the disease is disappearing.

 3. Creutzfeldt-Jakob disease: Of more general significance are the documented cases of iatrogenic (unintentionally introduced by medical procedures) transmission of CJD, for example, by use of prion-contaminated human pituitary–derived growth hormone pre pared from individuals who died from CJD. In addition, corneal transplants, implantation of contaminated brain electrodes, and blood transfusions have resulted in documented cases of disease transmission. Thus far, there has been no evidence of trans placental transmission or transmission by person-to-person con tact. In about 15 percent of CJD cases, the condition is inherited as a mutation in the PrP gene. However, most CJD cases are sporadic and have an unknown etiology (that is, they occur with no known exposure or mutational change). The incidence of sporadic CJD is low (about 1 to 2 per million population) but in those families with a PrP mutation, an attack rate of 50 to 100 percent is seen in those carrying the mutation. In contrast to CJD, all cases classified as GSS or FFI have involved inheritance of specific PrP mutations. Despite the inherited nature of the disease, brain tis sues from these patients are nevertheless infectious. Knockout mice lacking the gene that encodes PrP^C appear normal but are immune to infection with prions.

C. Pathology

Ingestion or other extracerebral exposure to prions results in significant multiplication of prion agents in the follicular dendritic cells within lymphoid tissues and in the spleen, but it is invasion of the central nervous system that results in the typical clinical effects. The basis for the pathogenic consequences of abnormal PrP^Sc deposition has not been clarified. Diseased brain tissue is characterized by accumulation of abnormal PrP^Sc in the form of amyloid fibrils in neuron cytoplasmic vesicles (see Figure 2) and in the form of extra cellular amyloid plaques. There is, in addition, extensive vacuolation within neurons, neuronal loss, and astroglial proliferation. The extensive destruction results in the characteristic spongiform appearance of gray matter in histologic sections. Whereas TSE amyloid plaques are morphologically similar to those of Alzheimer disease, the PrP gene is located on a different chromosome than the gene for the Alzheimer amyloid-β-protein precursor, and there is no nucleotide or amino acid homology between the two. Recent evidence suggests that these two proteins may physically interact with one another and participate in the same signaling or transport pathways in neurons.

Fig2. Electron micrograph of fibrillar prion proteins.

D. Clinical significance

 TSEs are a group of progressive, ultimately fatal, neurodegenerative diseases affecting humans and a number of animal species. The disease process is fundamentally the same in all TSEs, but their clinical manifestations and histopathologies differ. TSEs also share some similarities with conventional infectious diseases, but their differences are striking (Figure 3).

Fig3. Similarities and differences between conventional and unconventional agents. TSE = Transmissible spongiform encephalopathies. UV = ultraviolet.

1. Molecular basis of inherited TSEs: In each inherited TSE, specific, single amino acid substitutions or insertions of nucleotide repeat sequences are found in the PrP gene. These are thought to increase greatly (10⁶ -fold) the probability of transition to the infectious conformation. In the spontaneously occurring, sporadic disease (that is, with no known exposure to infectious material and no inheritance of a mutated PrP gene), it is proposed that the altered folding occurs randomly with low probability. Importantly, once formed, the abnormal PrP^Sc acquires both the ability to “multiply,” as well as the properties of an infectious agent. It has been recognized, however, that certain amino acid substitutions at one specific site increase susceptibility to infection.

2. Major symptoms: All TSEs involve deposition of the PrP^Sc protein. In the inherited forms, each PrP^Sc mutation is associated with a characteristic clinical phenotype. For example, the most prominent features of CJD are rapidly progressive dementia and behavioral disturbances, ending in death within 1 year. In GSS, ataxia is the more prominent feature, with death resulting in 2 to 6 years. FFI, also fatal within 1 year, has the additional symptom of uncontrollable insomnia. Although there is some difference in age of onset, all human TSEs (with the exception of BSE-associated vCJD) occur relatively late in life, typically between ages 40 and 60 years.

E. Laboratory identification

A presumptive diagnosis can be made on clinical grounds, but there is some overlap with other dementing illnesses. Routine laboratory tests of serum and cerebrospinal fluid are generally normal. The presence of infectious PrP^Sc in peripheral lymphatic tissue provides specimens for analysis without the need for brain biopsy. Currently, however, definitive diagnosis of these diseases is made by post mortem histopathologic examination of brain sections. Conversion from the wild-type PrP^C protein to the abnormal PrP^Sc is associated with changes in iron homeostasis within the host, leading to the hypothesis that iron-binding proteins could be used as a biomarker for TSE diseases.

F. Treatment and prevention

TSEs are invariably fatal, and no treatment is currently available that can alter this outcome. The unusually high resistance of the infectivity to most disinfecting agents makes transmission prevention by the usual infection control procedures ineffective. Current recommendations for decontamination of a CJD brain specimen are autoclaving at 132oC, plus immersion in either undiluted sodium hypochlorite or 1N sodium hydroxide. With respect to preventing possible transfer of BSE to humans, all animals showing signs of illness are destroyed, and preparation of animal feed from internal organs of potentially infected animals has ceased.

اخر الاخبار

اخبار العتبة العباسية المقدسة

وفد العتبة العباسية المقدسة يجري جولة في أروقة معرض بغداد الدولي للكتاب

شعبة التوجيه الديني النسوي تطلق برنامجًا قرآنيًّا لزائرات مرقد أبي الفضل العباس (عليه السلام)

جامعة الكفيل تطلق دورة تدريبية عن تقييم الأداء الجامعي لعدد من ملاكاتها

المجمع العلمي يقيم محفلًا قرآنيًا بذكرى ولادة الصادقين (صلوات الله عليهما)

المزيد

الآخبار الصحية

هل يتنبأ الذكاء الاصطناعي بأمراضنا قبل حدوثها؟

وداعا للنظارات.. قطرة عين واحدة قد تغير كل شيء ؟

دراسة تكشف تأثير "تيك توك" وتطبيقات الفيديو على سلوك الأطفال

"أسرار خفية" في الشاي الأخضر.. تغير قواعد الصحة والوزن

المزيد

الآخبار التكنلوجية

أول قطار يعمل بالهيدروجين في أميركا يدخل الخدمة رسميًا

أجهزة أبل القادمة.. "حصن منيع" في عصر الهجمات الرقمية !

روسيا: تطلق قمرين اصطناعيين بواسطة الصاروخ سويوز 2.1

ميزة ثورية.. أبل تدخل عالم قياس ضغط الدم

المزيد

مواضيع ذات صلة

Periprosthetic Joint Infection

Osteomyelitis in Long Bones

Vertebral Osteomyelitis

Human Hematopoietic Stem Cells

Embryonic Origin of Hematopoietic Stem Cells

نقي العظم (النخاع العظمي) Bone marrow

تكوين الدم Haematopoiesis

Gastrointestinal decontamination

تطبيقات البرايون ودوره المثير في مفهوم العقيدة المركزية

تصوير الأوعية التاجية

أدواء البريونات

Stages of Neutrophil Differentiation