Protein Misfolding And Diseases Flashcards
Alzheimer’s Disease
Extra cellular plaques= AB Plaque
Prion Disease
Prion plaque (PrP^sc)
Disease genes:PRNP
Risk Factor: Homozygosity at prion codon 129
Other neuro degenerative diseases due to protein aggregation
Parkinson’s: alpha-synuclein
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
Prion diseases in Humans
CJD
Kuru
GSS
FFI- fatal familial insomnia
Prion disease in animals
Scrapie- sheep
Bovine spongiform encephalopathy (BSE)- Mad Cow
Chronic wasting disease (CWD)- deer/elk
Prion Disease- Clinical Features
Dementia
Ataxia (lack of coordination)
Tremor
Myoclonus (unnatural jerking of muscles)
-fatal-
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
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
What is thought to have caused Kuru?
Ritual cannibalism
–> no new cases since cannibalism banned
Kuru- clinical features
Incubation time: 40 years
Transmission of kuru to primates
Similar pathology to scrapie
Three types of prion diseases
Infectious, Familial, Sporadic
Infection Prion Disease
Kuru
BSE
VCJD
CWD
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
Sporadic prion disease
CJD (most cases)
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
CJD- Features
Young age (29 yrs old)
Psychiatric symptoms
Prolonged course
Lots of plaque
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
What is a prion?
Proteinaceous infectious particle
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
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
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
What is the species barrier in prions diseases?
Cannot transfer mouse prions to hamster (barriers) –> but this is NOT an absolute barrier
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
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
Yeast Prions
Can see prions better in yeast than in mammals
- proof of infectivity
- basis of strains
- role of chaperones
- evolutionary function
Function of URE3 Prion
normal form- ure3
Prion form- URE3
Stops formation of ureidosuccinate
Function of PSI Prion
Normal- psi-
Prion- PSI+
Promotes termination of AA sequence–> adds in UAA
-Rnq1 and Swi1 have similar functions
Which amino acids are rich in prions?
Gln and Asn
Prions and Memory
Prions in sensory neurons can contribute to long-term facilitation
Prions and innante immunity
Prion-like aggregates activate and propagate antiviral innate immune response
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
What are the 2 primary pathological hallmarks of AD?
1) Neuritic plaque –> extra cellular AB
2) Neurofibrillary tangle –> intracellular tau
Where does AB come from in Alzheimer’s?
amyloid precursor protein (APP)
AB is cleaved from the APP protein
Where the two types of AB cleaved from APP?
Gamma cleavage –> mutate gamma secretase leads to build up of AB
Beta cleavage
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
What does GSM do in the processing of APP?
GSM- shift transcription to create shorter AB species which are the benign versions
What is the AB monoclonal antibody therapy for AD?
Many clinical trials have failed
Florbetapir (AMYVID)
New AB amyloid tracer no evidence of amyloid plaques in autopsy
What’s the catch with AMYVID as a AB amyloid tracer?
predictive but not diagnostic*
