Flashcards in Protein Misfolding And Diseases Deck (40):
1
Alzheimer's Disease
Extra cellular plaques= AB Plaque
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Prion Disease
Prion plaque (PrP^sc)
Disease genes:PRNP
Risk Factor: Homozygosity at prion codon 129
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Other neuro degenerative diseases due to protein aggregation
Parkinson's: alpha-synuclein
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Importance of prion disease
1) unprecedented infectious agent --> naked protein molecule with no DNA/RNA
2) only disease both infectious and genetic
3) rapid clinical course
4) relevant to other neuro degenerative disorders
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Prion diseases in Humans
CJD
Kuru
GSS
FFI- fatal familial insomnia
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Prion disease in animals
Scrapie- sheep
Bovine spongiform encephalopathy (BSE)- Mad Cow
Chronic wasting disease (CWD)- deer/elk
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Prion Disease- Clinical Features
Dementia
Ataxia (lack of coordination)
Tremor
Myoclonus (unnatural jerking of muscles)
-fatal-
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What is the incubation period for prion disease? Along with the duration of symptoms
Incubation period- years
(Transmitted by infection)
Duration of symptoms- 6 months- 5 years
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Why was Kuru most prevalent in women?
Women were ingesting brain and spinal areas of the dead body --> where you find the infection
Men were ingesting muscles (stronger parts of the body) --> don't find the disease there
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What is thought to have caused Kuru?
Ritual cannibalism
--> no new cases since cannibalism banned
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Kuru- clinical features
Incubation time: 40 years
Transmission of kuru to primates
Similar pathology to scrapie
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Three types of prion diseases
Infectious, Familial, Sporadic
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Infection Prion Disease
Kuru
BSE
VCJD
CWD
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Familial Prion disease
CJD (10% of the cases)
GSS
FFI
-inherited by autosomal dominant gene
-point or insertion all mutations of the prion gene
-can be infections even if it arises spontaneously thru a mutation
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Sporadic prion disease
CJD (most cases)
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Mad Cow Disease or BSE- History
1st case in UK (where majority of cases were) --> now spread to other European countries and Japan
Spread from ruminant-derived feed
Origin from sheep scrapie or spontaneous BSE
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CJD- Features
Young age (29 yrs old)
Psychiatric symptoms
Prolonged course
Lots of plaque
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What is the prion hypothesis?
Scrapie and related diseases are caused by a modified cellular protein that is infection in the absence of nucleic acid
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What is a prion?
Proteinaceous infectious particle
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Features of PrPc (cellular/normal)
Normal cell surface protein
Unknown function
Not infectious (causes inherited version)
Protease-sensitive
Monomeric
3% Beta sheet
40% alpha helix
X-Ray structure determined
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Features of scrapie PrP
Present only in diseased brain
Infectious protein (prion)
Protease-resistant (PrP 27-30)
Aggregated
40% Beta sheet
30% alpha helix
No high resolution structure determined
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Propagation of prions
-distinct from inheritance of nucleic acid sequence
-highly specific
- species barrier (due to mismatch between PrPc and PrPsc)
-strains- one primary sequence can result in multiple tertiary structures
-the PrPsc acts like a molecular template to duplicate
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What is the species barrier in prions diseases?
Cannot transfer mouse prions to hamster (barriers) --> but this is NOT an absolute barrier
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Characteristics of prion strains
Distinct incubation times
Patterns of neuropathology in a common host
^not due to an agent-specific nucleic acid
Just enciphered into distinct conformations--> PK cleavage site and glycoform distribution
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Nucleated polymerization of prion propagation
Addition of seeds (nuclei) --> eliminates usual lag phase and accelerates polymerization
Conformation of the seed determines the structure of the polymer
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Yeast Prions
Can see prions better in yeast than in mammals
-proof of infectivity
-basis of strains
-role of chaperones
-evolutionary function
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Function of URE3 Prion
normal form- ure3
Prion form- URE3
Stops formation of ureidosuccinate
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Function of PSI Prion
Normal- psi-
Prion- PSI+
Promotes termination of AA sequence--> adds in UAA
-Rnq1 and Swi1 have similar functions
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Which amino acids are rich in prions?
Gln and Asn
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Prions and Memory
Prions in sensory neurons can contribute to long-term facilitation
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Prions and innante immunity
Prion-like aggregates activate and propagate antiviral innate immune response
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Proteins with prion-like properties in neuro degenerative diseases
AB (Alzherimer's)
Alpha-synuclein (Parkinson's)
Tau- tauopathies
Htt- Huntingtons
Seeded polymerization in vitro --> inoculation and implant
Transmission between cells in culture --> thru exocytosis, anterograde transport, retrograde transport
PrPc + PrPSc --> prion rods --> PrP amyloid plaques
Alpha-syn + alpha-syn (prion) --> alpha-syn fibrils (prion) --> Lewy Body
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What are the 2 primary pathological hallmarks of AD?
1) Neuritic plaque --> extra cellular AB
2) Neurofibrillary tangle --> intracellular tau
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Where does AB come from in Alzheimer's?
amyloid precursor protein (APP)
AB is cleaved from the APP protein
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Where the two types of AB cleaved from APP?
Gamma cleavage --> mutate gamma secretase leads to build up of AB
Beta cleavage
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What are the 2 types of secretase inhibitors used as treatments for AD?
BACE Inhibitor- levels of all AB species reduced uniformly
GSI (gamma secretase inhibitor)- levels of AB species reduced but longer AB to smaller AB ratio increases
^^longer AB is the pathogenic version of the protein --> shorter are benign
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What does GSM do in the processing of APP?
GSM- shift transcription to create shorter AB species which are the benign versions
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What is the AB monoclonal antibody therapy for AD?
Many clinical trials have failed
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Florbetapir (AMYVID)
New AB amyloid tracer no evidence of amyloid plaques in autopsy
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