Prions and associated diseases

Dr. Hala Al Daghistani

Prions (Proteinacious infectious organism ) with diameters of 5–100 nm or less,

are infective, malfolding protein particles representing a rare cause of

encephalopathic disease that can arise as either

a) sporadic mutations in human beings

b) inherited disease

c) derived from contaminated meat

d) Iatrogenically introduced.

The normal prion protein, which is designated as PrPc, is

a 35kD membrane glycoprotein

water-soluble

proteinase-sensitive.

PrPc is encoded by the PRNP gene on chromosome 20 and probably plays

a role in multiple cellular functions, including cell adhesion, ion channel

activity, and neuronal excitability.

Abnormal prions, designated as PrPSc

or PrPTSE

, result from a change in

the folding pattern of PrPc, which makes it

Resistant to the action of proteases

Precipitate as insoluble amyloid.

Amyloid are aggregates of proteins that become folded into a shape that allows

many copies of that protein to stick together forming fibrils. Pathogenic

amyloids form when previously healthy proteins lose their

normal physiological functions and form fibrous deposits in plaques around neural

cells which can disrupt the healthy function of these cells. This conversion results

in neuronal degeneration and loss by an unknown mechanism.

Prions can remain viable even in formalinized brain tissue for many years. They

are Resistant to ionizing radiation, Boiling, and many Common disinfectants.

Prions have Not been grown in cell culture.

Biologic and Physical Properties of Prions

Chronic progressive pathology without remission or recovery

No inflammatory response

No alteration in pathogenesis by immunosuppression or immunopotentiation

Transmissible to experimental animals

No interferon production or interference by conventional viruses

Unusual resistance to ultraviolet irradiation, alcohol, formalin, boiling,

proteases, and nucleases

Can be inactivated only by soaking in 2.0 N NaOH for 1 hour, Rinsing, and

autoclave at 134 oC for 1 hour.

Transmissible

Once PrPSc

is generated endogenously or introduced into the body from the

environment, it converts normal prions into abnormal ones. This conversion begins

with the initial production of a small polymer of misfolded prions, (a seed),

perhaps no more than 28 molecules. This seed converts normal adjacent prions into

abnormal ones by an unknown mechanism.

Prion Diseases associated with human and animals

A group of progressive degenerative diseases of the CNS has been shown to be

caused by prions including:

Kuru A disease that are resulted from the consumption of human brain. It is a

subacute, progressive neurologic disease of the people of the Eastern Highlands of

Guinea.

The disease was brought to the attention of the Western world in 1957.

Although the illness was localized and decreasing in incidence, its study has

thrown light on the transmissibility and infectious nature of similar

encephalopathies.

Epidemiologic studies indicated that kuru usually afflicted adult women, or

children of either sex.

The symptoms and signs were - Ataxia اختالج الحركة

- Hyperreflexia فرط المنعكسات

- Spasm

- progressive dementia

- starvation, and death.

Pathologic examination revealed changes only in the CNS, with diffuse

neuronal degeneration and spongiform changes of the cerebral cortex and basal

ganglia. No inflammatory response was apparent.

Inoculation of infectious brain tissue into primates produced a disease that

caused similar neurologic symptoms and pathologic manifestations after an

incubation period of approximately 40 months.

Epidemiologic studies indicated that transmission of the disease in humans was

associated with ingestion of a soup made from the brains of dead relatives

and eaten in honor of the deceased.

Clinical disease developed 4 to 20 years after exposure. Since the elimination

of cannibalism اكم نحوو انبشر from the Fore culture, kuru has disappeared.

Creutzfeldt–Jakob disease (CJD) is the most common form of prion

disease with an incidence of around one per million, and is primarily acquired by

spontaneous malfolding in the PrPc protein causing it to become the abnormal

prion protein PrPsc

.

The disease is a progressive, fatal illness of the CNS that is seen most

frequently in the sixth and seventh decades of life.

The initial clinical manifestations are a change in cerebral function, usually

diagnosed initially as a psychiatric disorder.

- Forgetfulness نسيان and disorientation progress to overt dementia انخرف انعهني

- changes in gait مشية

- increased tone in the limbs

- involuntary movement

- seizures.

The disorder usually runs a course of 4–7 months, eventually leading to

paralysis, wasting, pneumonia, and death.

The mode of acquisition is unknown, but it occurs both sporadically (85%) and

in a familial pattern (15%).

Infection has also been transmitted by

- dura mater grafts

- corneal transplants

- contact with contaminated electrodes or instruments used in

neurosurgical procedures

- pituitary-derived human growth hormone (The latter was responsible

for more than 100 cases).

The incubation period of the disease is approximately 3 to greater than 20

years.

High levels of infectious agent have been found, especially in the brain, where

they may reach 107 infectious doses per gram of brain tissue.

There is no evidence of transmission by direct contact or airborne spread.

Brains from patients with Creutzfeldt–Jakob disease have the birefringent rods

.and fibrillar structures عصيات ثنائية االنكسار

Therapy: There is no effective therapy for Creutzfeldt–Jakob disease, and all

cases have been fatal.

Stereotactic neurosurgical equipment, especially that used in patients with

undiagnosed dementia, should not be reused.

In addition, organs from patients with undiagnosed neurologic disease should

not be used for transplants.

Growth hormone from human tissue has now been replaced by a recombinant

genetically engineered product.

The agent of Creutzfeldt–Jakob disease has not been transmitted to animals by

inoculation of body secretions

LABORATORY DIAGNOSIS OF CJD

Diagnosis: Identification of PrPsc

and antibodies directed against it may become

a useful diagnostic adjunct to neuropathologic examination of brain tissue.

Pathologic examination of brain tissue is the only definitive diagnostic test.

CSF Parameters:

1. Protein and glucose concentration is normal and there is no pleocytosis.

2. The most useful CSF marker of CJD is elevation of protein 14-3-3.

These brain proteins consist of a group of highly conserved proteins

composed of several isoforms that are involved in cell proliferation,

differentiation and signal transduction and regulates neurotransmitter

synthesis. Detectable 14-3-3 protein in the cerebrospinal fluid (CSF) is

indicative of relatively rapid neuronal destruction.

3. Neuron-specific enolase (NSE)

4. microtubule associated protein tau

5. S-100 protein are also elevated in the CSF but their sensitivity is lower

than 14-3-3.

DNA sequencing

Mutations of the PRNP gene can be detected by sequencing of DNA extracted

from blood, brain, and other tissues.

Brain biopsy

A definitive diagnosis can be made by microscopic examination of brain tissue

showing the characteristic spongy change.

Scrapie ( ,) انراعوشاعتالل اندماغ االسفنجي انقابم نالنتقال resulted from the consumption

of infected beef (a disease of sheep involving the CNS, characterized by a lack of

coordination causing affected animals to rub against trees and other objects for

support).

Brain extracts from scrapie-infected animals contain PrPsc

, which is not

found in the brains of normal animals; PrPsc

is the prion that is responsible

for transmission and infection.

The conformational change is also the way that prions multiply; that is,

contact with PrPsc

results in a conformational change of the normal host cell

protein PrPc and the formation of additional PrPsc

.

During scrapie infection, prion protein may aggregate into rods and form

filamentous structures termed scrapie-associated fibrils, which are found

in membranes of scrapie-infected brain tissues. .

Bovine spongiform encephalopathy (BSE) اعتالل الدماغ اإلسفنجي البقري

BSE is a transmissible, neuro-degenerative fatal brain disease of cattle. The

disease has a long incubation period of 4-5 years and it is fatal for cattle within

weeks to months of its onset. Unfortunately, the prion that causes BSE survived the

heat of cooking and was transmitted to humans who consumed infected bovine

neural tissue or bone marrow (both are sometimes found in processed meats,

depending on the rendering procedures used).

The source of the emerging epidemic was soon traced to a food supplement that

included meat and bone meal from dead sheep.

In addition to the incoordination and apprehension تخوف, the cows exhibited

hyperreflexia فرط انمنعكسات , muscle fasciculations انتحزو , tremorsاالرتعاش , and

weight loss. Autonomic dysfunction was frequently manifested as reduced

rumination قهة االجترار , bradycardia and other cardiac arrhythmias.

Varying degrees of neuronal loss occur. The diseases are known as “spongiform”

encephalopathies because of the vacuolar changes in the cortex and cerebellum.

LBORATORY DIAGNOSIS

All modern tests for BSE are based on antibodies to select prion protein in

tissue