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MoMF > Protein Misfolding And Diseases > Flashcards

Protein Misfolding And Diseases Flashcards

1
Q

Alzheimer’s Disease

A

Extra cellular plaques= AB Plaque

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2
Q

Prion Disease

A

Prion plaque (PrP^sc)

Disease genes:PRNP

Risk Factor: Homozygosity at prion codon 129

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3
Q

Other neuro degenerative diseases due to protein aggregation

A

Parkinson’s: alpha-synuclein

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4
Q

Importance of prion disease

A

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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5
Q

Prion diseases in Humans

A

CJD

Kuru

GSS

FFI- fatal familial insomnia

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6
Q

Prion disease in animals

A

Scrapie- sheep

Bovine spongiform encephalopathy (BSE)- Mad Cow

Chronic wasting disease (CWD)- deer/elk

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7
Q

Prion Disease- Clinical Features

A

Dementia

Ataxia (lack of coordination)

Tremor

Myoclonus (unnatural jerking of muscles)

-fatal-

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8
Q

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

A

Incubation period- years
(Transmitted by infection)

Duration of symptoms- 6 months- 5 years

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9
Q

Why was Kuru most prevalent in women?

A

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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10
Q

What is thought to have caused Kuru?

A

Ritual cannibalism

–> no new cases since cannibalism banned

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11
Q

Kuru- clinical features

A

Incubation time: 40 years

Transmission of kuru to primates

Similar pathology to scrapie

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12
Q

Three types of prion diseases

A

Infectious, Familial, Sporadic

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13
Q

Infection Prion Disease

A

Kuru

BSE

VCJD

CWD

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14
Q

Familial Prion disease

A

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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15
Q

Sporadic prion disease

A

CJD (most cases)

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16
Q

Mad Cow Disease or BSE- History

A

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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17
Q

CJD- Features

A

Young age (29 yrs old)

Psychiatric symptoms

Prolonged course

Lots of plaque

18
Q

What is the prion hypothesis?

A

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

19
Q

What is a prion?

A

Proteinaceous infectious particle

20
Q

Features of PrPc (cellular/normal)

A

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
Q

Features of scrapie PrP

A

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
Q

Propagation of prions

A
  • 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
Q

What is the species barrier in prions diseases?

A

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

24
Q

Characteristics of prion strains

A

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
Q

Nucleated polymerization of prion propagation

A

Addition of seeds (nuclei) –> eliminates usual lag phase and accelerates polymerization

Conformation of the seed determines the structure of the polymer

26
Q

Yeast Prions

A

Can see prions better in yeast than in mammals

  • proof of infectivity
  • basis of strains
  • role of chaperones
  • evolutionary function
27
Q

Function of URE3 Prion

A

normal form- ure3

Prion form- URE3

Stops formation of ureidosuccinate

28
Q

Function of PSI Prion

A

Normal- psi-

Prion- PSI+

Promotes termination of AA sequence–> adds in UAA

-Rnq1 and Swi1 have similar functions

29
Q

Which amino acids are rich in prions?

A

Gln and Asn

30
Q

Prions and Memory

A

Prions in sensory neurons can contribute to long-term facilitation

31
Q

Prions and innante immunity

A

Prion-like aggregates activate and propagate antiviral innate immune response

32
Q

Proteins with prion-like properties in neuro degenerative diseases

A

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
Q

What are the 2 primary pathological hallmarks of AD?

A

1) Neuritic plaque –> extra cellular AB

2) Neurofibrillary tangle –> intracellular tau

34
Q

Where does AB come from in Alzheimer’s?

A

amyloid precursor protein (APP)

AB is cleaved from the APP protein

35
Q

Where the two types of AB cleaved from APP?

A

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

Beta cleavage

36
Q

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

A

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
Q

What does GSM do in the processing of APP?

A

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

38
Q

What is the AB monoclonal antibody therapy for AD?

A

Many clinical trials have failed

39
Q

Florbetapir (AMYVID)

A

New AB amyloid tracer no evidence of amyloid plaques in autopsy

40
Q

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

A

predictive but not diagnostic*

MoMF (25 decks)

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