Lec 10 Prions Flashcards
Prion diseases
3 manifestations
Prion diseases: fatal infectious NEURODEGENERATIVE DISORDERS in man and animals. PrP = prion protein
3 manifestations: acquired, sporadic, genetic
ACQUIRED: infection from outside, exogenous
eg. Kuru, BSE, CWD (Cronic Wasting Disease)
Canada has BSE and CWD
SPORADIC: SPONTANEOUS CHANGE in PrP CONFORMATION, endogenous. Mainly in humans. 1 per 1 million people.
GENETIC: GERMLINE MUTATION PrP, endogenous. Acquired from outside
Viruses are not sporadic or genetic but Prions are
Prions have long incubation time (2-3 years), short clinical phase, no preclinical diagnosis, no therapy
Prions and Disorders of the CNS
Other name for Prions: Transmissible Spongiform Encephalopathies (TSEs)
Prions lead to CNS disorders. Most are in the BRAIN. Very rare in humans, difficult to diagnose.
Compartmentalization yet all 3 forms are infectious!
(Acquired, Sporadic, Genetic)
- transmissible within species e.g. BSE
- transmissible between species eg. Mad Cow disease
Species barrier and prion strains!!!
Prion-like: EPIGENETIC MODE of INFO TRANSFER
- The mechanism that changes the prion structure encodes LONG TERM MEMORY.
- Prion-like aggregates (antiviral INNATE IMMUNITY)
Prion specifics
Prions – PROTEINACEOUS INFECTIOUS PARTICLES. Infectious protein pathogens that fundamentally differ from bacteria, viruses or fungi.
UV activation normally destroys viral genome. The SCRAPIE (PrPSc mutation) ACTIVITY is UNAFFECTED by UV light because Prions do not have NA + genome.
Cause and transmit fatal neurodegenerative brain diseases. No one is safe and Prion infections are a fast, 100% deadly disease!
PRION-LIKE BEHAVIOR is SEEN in ALL MAJOR NEURODEGENERATIVE diseases
eg. AD, Parkingson’s D, ALS, Huntingson’s D
PrP Conformations
Prions compose of Protein CONFORMATIONAL Diseases
Prions are infectious, purified from brains of victims, unknown structure. UNNECESSARY FOR SURVIVAL, proposed to offer NEUROPROTECTIVE roles.
PrPc: NORMAL cellular ISOFORM that is NOT INFECTIOUS, made of α helices.
PrPSc (SCRAPIE): PATHOLOGICAL ISOFORM is infectious, made of ß-SHEETs. Converts PrPc molecules to more PrPSc!
Derived from PrPc. ß-SHEETs. are MORE STABLE than α helices so ß-SHEETs causes PrPc AGGREGATION.
~ 15 PrPSc make 1 Prion
Natural PrPc protein
PrPSc is formed when you digest N terminus from PrPc.
PrPc and PrPSc have opposite properties.
PrPc is α-helical, soluble, PK sensitive, no aggregation not infectious
PrPSc is made of ß-sheets, insoluble, relatively PK resistant, aggregation infectious
PrPc function unknown! No loss of function. If you add PrPSc to a brain w/ no PrPc no Prion disease is made.
PrPc is mostly involved in signalling cascade, animals can live without it.
PrPSc Replication Models
Seed nucleation
Template-assisted model
Seed nucleation
PrPSc goes to nucleus and converts PrPc into PrPSc, cause + feedback to form aggregates.
PrPSc is an array of beta sheets, which make the new form more stable!
Template-assisted model
When PrPc is captured by template PrPSc to cause conversion (structure change) and this speeds to the whole molecule. The New PrPSc refolds.
Path
PrPc is normally anchored to GPI, degraded in lysosome. When PrPSc conformation occurs, it cannot be degraded anymore b/c of its more stable beta sheet form. There is a balance between degradation and synthesis
In the COMPARTMENT OF CONVERSION the direct contact between PrPSc turns PrPc into another PrPSc
Prion Pathology
Spongiform Degeneration:
- intracellular vacuolisation
 - loss of neurons. Cannot replace differentiated neurons!
- astrocytic gliosis (proliferation).
- eventually amyloidplaques (PrPSc) deposits
in the Terminal state, Prions cause brain to have holes, where the neurons died. If you stain for the plaques, they are huge
Prion form differentiation between PrPc and PrPSc using tissue from CNS
PrPSc remains in PK resistance test, shows + test
You can use ultracentrifugation. PrPSc is insoluble while PrPc is still soluble.
There are no blood tests, you need brain tissue.
Prion Pathways towards the CNS
Begins w/ ORAL or INTERNAL (endogenous) PRION infection
Directly into CNS by INVADING NERVES OR
Prions REPLICATE in LYMPHATIC SYSTEM, get SECONDARY access to NERVES OR
There should be a DIRECT WAY BY BLOOD
When you eat prions
eg. Kuru, BSE
PRIONS have no problems moving along gut.
Macrophages, Follicular Dendritic Cells, lymphocytes catalyze prion replication, all 3 close to nerve fibre.
PrPCs go to ganglia via ENTERIC NERVOUS SYSTEM, then spinal cord and brain.
Brown regions in the spinal cord are Prions
Human Prion Diseases
(sporadic, genetic, acquired)
Manifestation, clinical phase and incidence
- SPORADIC
CJD: Creudtfeltz-Jakob Syndrome
Sporadic progressive dementia (cortex) EEG (final) pos. Takes 2-3 months to die vs 10 years in Alzeimer’s
- GENTIC
CJD/GSS/FFI genetic progressive ataxia
- ACQUIRED cases (e.g. hGH, dura)
- Kuru (ritualistic cannibalism) ataxia
- vCJD (BSE exposition) causes psychotic symptoms, ataxia. vCJD is a ZOONOTIC PRION DISEASE
svCJD (iatrogenic)
Worldwide > 700 people die every year
Kuru
“Man-made” Prion Diseases
What kind of Prion?
KURU is prevalent in YOUNG and FEMALE patients. Thy cannot move anymore. KILLS MOTOR COORDINATION (CEREBELLUM), waisting caused starvation, all die of secondary problems.
Scrapie BSE’s epidemic form is NEOCANNIBALISM: when you feed cattle to cattle and eat those cattle!
Animal
Scrapie and BSE both involve ATAXIA
SCRAPIE also involves ITCHING, so the animal scratches itself.
CWD Chronic Waisting Disease
EXTREME HORIZONTAL TRANSMISSION =
MOST INFECTIOUS PRION disease! 1-3%
Prions found in muscles, feces
CWD started in Wyoming, moves north, will reach Albertan Caribou soon!
With higher CWD prevalence the population estimate decreases A LOT.
Zoonotic prion disease: vCJD
Zoonotic prion disease: vCJD
Patients were of Young age, atypical clinical course, characteristic pathology in brain, no exponential increase… Shows up around around 25 then decreases,
svCJD (iatrogenic): Blood (4) and lymphatic system
Also transmitted from blood products such as donated blood and injections!
