Protein Misfolding And Diseases

Question 1

Alzheimer’s Disease

Answer 1

Extra cellular plaques= AB Plaque

Question 2

Prion Disease

Answer 2

Prion plaque (PrP^sc)

Disease genes:PRNP

Risk Factor: Homozygosity at prion codon 129

Question 3

Other neuro degenerative diseases due to protein aggregation

Answer 3

Parkinson’s: alpha-synuclein

Question 4

Importance of prion disease

Answer 4

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

Question 5

Prion diseases in Humans

Answer 5

CJD

Kuru

GSS

FFI- fatal familial insomnia

Question 6

Prion disease in animals

Answer 6

Scrapie- sheep

Bovine spongiform encephalopathy (BSE)- Mad Cow

Chronic wasting disease (CWD)- deer/elk

Question 7

Prion Disease- Clinical Features

Answer 7

Dementia

Ataxia (lack of coordination)

Tremor

Myoclonus (unnatural jerking of muscles)

-fatal-

Question 8

What is the incubation period for prion disease? Along with the duration of symptoms

Answer 8

Incubation period- years
(Transmitted by infection)

Duration of symptoms- 6 months- 5 years

Question 9

Why was Kuru most prevalent in women?

Answer 9

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

Question 10

What is thought to have caused Kuru?

Answer 10

Ritual cannibalism

–> no new cases since cannibalism banned

Question 11

Kuru- clinical features

Answer 11

Incubation time: 40 years

Transmission of kuru to primates

Similar pathology to scrapie

Question 12

Three types of prion diseases

Answer 12

Infectious, Familial, Sporadic

Question 13

Infection Prion Disease

Answer 13

Kuru

BSE

VCJD

CWD

Question 14

Familial Prion disease

Answer 14

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

Question 15

Sporadic prion disease

Answer 15

CJD (most cases)

Question 16

Mad Cow Disease or BSE- History

Answer 16

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

Question 17

CJD- Features

Answer 17

Young age (29 yrs old)

Psychiatric symptoms

Prolonged course

Lots of plaque

Question 18

What is the prion hypothesis?

Answer 18

Scrapie and related diseases are caused by a modified cellular protein that is infection in the absence of nucleic acid

Question 19

What is a prion?

Answer 19

Proteinaceous infectious particle

Question 20

Features of PrPc (cellular/normal)

Answer 20

Normal cell surface protein

Unknown function

Not infectious (causes inherited version)

Protease-sensitive

Monomeric

3% Beta sheet

40% alpha helix

X-Ray structure determined

Question 21

Features of scrapie PrP

Answer 21

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

Question 22

Propagation of prions

Answer 22

• 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

Question 23

What is the species barrier in prions diseases?

Answer 23

Cannot transfer mouse prions to hamster (barriers) –> but this is NOT an absolute barrier

Question 24

Characteristics of prion strains

Answer 24

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

Question 25

Nucleated polymerization of prion propagation

Answer 25

Addition of seeds (nuclei) --> eliminates usual lag phase and accelerates polymerization Conformation of the seed determines the structure of the polymer

Question 26

Yeast Prions

Answer 26

Can see prions better in yeast than in mammals - proof of infectivity - basis of strains - role of chaperones - evolutionary function

Question 27

Function of URE3 Prion

Answer 27

normal form- ure3 Prion form- URE3 Stops formation of ureidosuccinate

Question 28

Function of PSI Prion

Answer 28

Normal- psi- Prion- PSI+ Promotes termination of AA sequence--> adds in UAA -Rnq1 and Swi1 have similar functions

Question 29

Which amino acids are rich in prions?

Answer 29

Gln and Asn

Question 30

Prions and Memory

Answer 30

Prions in sensory neurons can contribute to long-term facilitation

Question 31

Prions and innante immunity

Answer 31

Prion-like aggregates activate and propagate antiviral innate immune response

Question 32

Proteins with prion-like properties in neuro degenerative diseases

Answer 32

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

Question 33

What are the 2 primary pathological hallmarks of AD?

Answer 33

1) Neuritic plaque --> extra cellular AB | 2) Neurofibrillary tangle --> intracellular tau

Question 34

Where does AB come from in Alzheimer's?

Answer 34

amyloid precursor protein (APP) AB is cleaved from the APP protein

Question 35

Where the two types of AB cleaved from APP?

Answer 35

Gamma cleavage --> mutate gamma secretase leads to build up of AB Beta cleavage

Question 36

What are the 2 types of secretase inhibitors used as treatments for AD?

Answer 36

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

Question 37

What does GSM do in the processing of APP?

Answer 37

GSM- shift transcription to create shorter AB species which are the benign versions

Question 38

What is the AB monoclonal antibody therapy for AD?

Answer 38

Many clinical trials have failed

Question 39

Florbetapir (AMYVID)

Answer 39

New AB amyloid tracer no evidence of amyloid plaques in autopsy

Question 40

What's the catch with AMYVID as a AB amyloid tracer?

Answer 40

*****predictive but not diagnostic******