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