Tema 28. Priones

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Tema 28. Priones
Características generales Estructura y ciclo de
multiplicación. Patogenia. Inmunidad. Cuadros
clínicos. Diagnóstico. Tratamiento.
Epidemiología y Profilaxis. (Viroides)
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• Prions and viroids are unconventional infectious
  agents
• Prionsinfectious proteins that cause a group of
  diseases of the brain and nervous system called
  Transmissible Spongiform Encephalopathies (TSEs)
• Viroidssmall, pathogenic RNAs that cause
  viruslike diseases in plants

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Características Priones

• Proteínas modificadas del hospedador que puede
  transmitir la enfermedad.
• Prión pequeña partícula infecciosa proteica.
  (PrP stands for proteinaceous infectious
  particle)
• Humanos
• Kuru
• Enfermedad de Creutzfeldt-Jakob (ECJ)
• Animales
• Encefalopatía espongiforme bovina (vacas locas)

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Tertiary Structure of PrPc and PrPres
Estructura y ciclo de multiplicación
Two Distinct Conformations of the Prion Protein
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PRNP gene encodes PrPC

• PRNP gene located on chromosome 20 of humans
• Codes for a 254 AA protein.
• It is unique (no other proteins of similar
  homology in the database)
• PrPC is targeted via a secretory pathway to the
  cell surface of neurons and other cell types
• A glycosylinositol phospholipid anchors it into
  the membrane.

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Biochemical Analysis of the Prion Amino Acid
Sequence
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Hypothetical Model showing PrPc Involvement in
the Secretory Pathway of Cells
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Patogenia

• Incubation period of TSEs (with the exception of
  vCJD) is long (20-56 years)
• South Fore tribe members still getting Kuru some
  39-56 years after the cessation of cannibalism

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Histological/Brain Changes of TSEs
Patogenia

• Infected brains become spongiform (the brain has
  vacuolesclear zones, similar to a sponge)
• Neuronal loss
• Astrocystosis (spread of astrocytes to damaged
  tissues in the brain)
• Amyloid plaquesformation of PrPres threadlike
  aggregates

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Spongiosis
Brain tissues showing histopathologic changes
found in bovine spongiform encephalopathy.
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Diagram of the Major Regions of the Human Brain
Affected by the Different TSEs
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Brain Changes

• Depending upon what region of the brain is
  affected
• e.g. memory is affected when the cerebral cortex
  is infected
• No inflammation or immune defense against prions
  exists
• Natural proteins (body does not recognize as
  foreign antigens)
• Prion proteins are only harmful when they are
  converted to PrPres

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PRIONES
Depósitos de proteínas priónicas
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Inmunidad

• None of the TSEs evoke an immune response
• Prions cause a noninflammatory process that
  results in vacuolation or spongiosis in the gray
  matter of the brain

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Fore Child with Symptoms of Ambulant Stage
Cuadros Clínicos
A Fore child with symptoms of the ambulant stage
of Kuru.
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Clinical Signs and Symptoms of Variant
Creutzfeldt-Jakob Disease (Variant CJD)

• 50 of variant CJD patients die before the age of
  30
• average age of death is 28
• Patients suffering from classic CJD die at an
  average of 68 years

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Symptoms of Variant CJD

• Anxiety
• Memory loss
• Mood changes
• Depression
• Neurological signs
• Twitching
• Spasms (jerky movements)
• Posture and gait abnormalities (motor
  difficulties)

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Final Symptoms of Variant CJD

• Loss of speech
• Stupor
• Persistent vegetative state (coma)
• Death (14 months after symptoms appear)

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Diagnóstico de CJD

• Most patients referred to a psychiatrist because
  of behavioral changes
• Definitive diagnosisprion positive
  immunostaining of biopsy material from
• Tonsil
• Spleen
• Lymph nodes
• Electroencefalografíalooking for slow or
  negative brain wave activity
• Resonancia magnéticalooking for brain lesions
• LCRlooking for elevated levels of neuronal,
  astrocytic and glial proteins
• Elevated levels are a consequence of damage to
  the blood brain barrier

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Gold Standard of Diagnosis is Postmortem
Examination of Brain Tissues
Detection of PrPres by Western blot analysis.
Samples of human brain tissues from a diseased
individual suspected of variant CJD.
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Human Genetics Codon 129

• 50 known mutations in the PRNP gene
• PRNP codon 129 appears to act as a genetic
  susceptibility factor (codes for methionine or
  valine at position 129 of the PrPC).
• All people suffering from vCJD acquired through
  consuming prion-contaminated beef products were
  homozygous methionine at codon 129

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Steps Toward Treatment and Vaccination

• No drug therapies available.
• Treatment is supportive
• No vaccine available
• PrPC antibodies injected into the brains of mice
  cause neurotoxicity

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Epidemiología y Profilaxis

• Prions are highly resistant to routine methods
  of decontamination
• Not inactivated by proteases, organic solvents,
  alkaline cleaners, ultraviolet radiation,
  ethanol, formaldehyde or extremely high
  temperatures (e.g. greater than 100 oC
  sterilization for one hour at 121 oC in an
  autoclave does not kill prions)

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Typical Decontamination Protocol that Researchers
Use

• Tissues, infectious waste, and instruments used
  in the processing of prion-contaminated samples
  are decontaminated in
• 1 N NaOH or undiluted fresh household bleach
  followed by autoclaving at 132 oC for 4.5 hours

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ACCIÓN DE LOS AGENTES FÍSICOS Y QUÍMICOS SOBRE
PRIONES.
COMPARACION VIRUS VS PRIONES VIRUS PRION
Filtrable (infeccioso) Sí Si
Presencia Acido Nucleico Sí No
Presencia de proteínas Sí Sí
Desinfección con
Formaldehído Sí No
Proteasas Algunos No
Calor (80ºC) La mayoría No
Radiaciones ionizantes y UV Sí No
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Transmission

• Infection
• diet, vCJD
• Iatrogenic means (e.g. surgery)
• Growth hormone injections
• Corneal transplants
• Inherited
• Genetic CJD
• Gerstmann-Straussler-Scheinker Disease (GSS)
• Fatal Familial Insomnia (FFI)
• Sporadic forms
• CJD

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Transmission
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Species Barrier Bovine Spongiform
Encephalopathy (BSE) and Variant
Creutzfeldt-Jakob Disease (Variant CJD)

• Transmissibility among species is easy
• Transmission can occur between different species
• Origin of BSE unclear
• Accepted hypothesis is that BSE came from cattle
  ingesting scrapie-contaminated bone meal derived
  from sheep offal fed to young calves

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ENCEFALOPATÍAS ESPONGIFORMES TRANSMISIBLES

• HOMBRE
• Kuru.
• Enfermedad de Creutzfeldt-Jacob (ECJ).
• Síndrome de Gerstmann-Straussler (ECJ
  hereditaria).
• Síndrome de insomnio familiar fatal.
• Nueva variante de la Enfermedad de
  Creutzfeldt-Jacob (nv ECJ).
• ANIMALES
• Scrapie.
• Encefalopatía espongiforme bovina (Enfermedad de
  las vacas locas).

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nvECJ

• Consumo de derivados bovinos con EEB amígdalas,
  retina, tejido nervioso.
• Homocigotos met en el codón 129.
• Diferencias

nvECJ ECJ
Edad 15-35 55-65
Duración 14 meses 4,5 meses
Predomina Síntomas psiquiátricos Demencia
Alteraciones EEG NO SI
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ENCEFALOPATÍAS ESPONGIFORMES SUBAGUDASPRIÓN-VIRIÓ
N

• SIMILITUDES
• Transmisibles.
• Muy pequeños.
• Filtrables.
• Dependientes de la célula huésped.
• Sin capacidad de
• Generar energía.
• Síntesis proteica.

• DIFERENCIAS
• No evidencia de partículas virales.
• Ácidos nucleicos no detectables.
• Muy resistentes.
• No inducen reacción inflamatoria/respuesta
  inmunitaria.