Protein Misfolding And Diseases Flashcards Preview

MoMF > Protein Misfolding And Diseases > Flashcards

Flashcards in Protein Misfolding And Diseases Deck (40):
1

Alzheimer's Disease

Extra cellular plaques= AB Plaque

2

Prion Disease

Prion plaque (PrP^sc)

Disease genes:PRNP

Risk Factor: Homozygosity at prion codon 129

3

Other neuro degenerative diseases due to protein aggregation

Parkinson's: alpha-synuclein

4

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

5

Prion diseases in Humans

CJD

Kuru

GSS

FFI- fatal familial insomnia

6

Prion disease in animals

Scrapie- sheep

Bovine spongiform encephalopathy (BSE)- Mad Cow

Chronic wasting disease (CWD)- deer/elk

7

Prion Disease- Clinical Features

Dementia

Ataxia (lack of coordination)

Tremor

Myoclonus (unnatural jerking of muscles)

-fatal-

8

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

9

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

10

What is thought to have caused Kuru?

Ritual cannibalism
--> no new cases since cannibalism banned

11

Kuru- clinical features

Incubation time: 40 years

Transmission of kuru to primates

Similar pathology to scrapie

12

Three types of prion diseases

Infectious, Familial, Sporadic

13

Infection Prion Disease

Kuru

BSE

VCJD

CWD

14

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

15

Sporadic prion disease

CJD (most cases)

16

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

17

CJD- Features

Young age (29 yrs old)

Psychiatric symptoms

Prolonged course

Lots of plaque

18

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

19

What is a prion?

Proteinaceous infectious particle

20

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

21

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

22

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

23

What is the species barrier in prions diseases?

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

24

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

25

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

26

Yeast Prions

Can see prions better in yeast than in mammals

-proof of infectivity
-basis of strains
-role of chaperones
-evolutionary function

27

Function of URE3 Prion

normal form- ure3

Prion form- URE3

Stops formation of ureidosuccinate

28

Function of PSI Prion

Normal- psi-

Prion- PSI+

Promotes termination of AA sequence--> adds in UAA

-Rnq1 and Swi1 have similar functions

29

Which amino acids are rich in prions?

Gln and Asn

30

Prions and Memory

Prions in sensory neurons can contribute to long-term facilitation

31

Prions and innante immunity

Prion-like aggregates activate and propagate antiviral innate immune response

32

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

33

What are the 2 primary pathological hallmarks of AD?

1) Neuritic plaque --> extra cellular AB

2) Neurofibrillary tangle --> intracellular tau

34

Where does AB come from in Alzheimer's?

amyloid precursor protein (APP)

AB is cleaved from the APP protein

35

Where the two types of AB cleaved from APP?

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

Beta cleavage

36

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

37

What does GSM do in the processing of APP?

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

38

What is the AB monoclonal antibody therapy for AD?

Many clinical trials have failed

39

Florbetapir (AMYVID)

New AB amyloid tracer no evidence of amyloid plaques in autopsy

40

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

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