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Infection > Lecture 11.1: Prions > Flashcards

Lecture 11.1: Prions Flashcards

1
Q

What are Prions?

A

Prions are mis-folded proteins with the ability to transmit their mis-folded shape onto normal variants of the same protein

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2
Q

What are Prion Diseases?

A
  • Neurodegenerative diseases

* Alternatively known as Transmissible Spongiform Encephalopathy (TSE)

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3
Q

What are some Examples of Prion Diseases? (4)

A
  • Creutzfeldt-Jakob disease (CJD) & variant Creutzfeldt-Jakob disease (vCJD)
  • Kuru
  • Fatal Familial Insomnia (FFI)
  • Gerstmann-Straussler-Scheinke syndrome (GSS)
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4
Q

What are Symptoms of Prion Diseases? (6)

A
  • Anxiety & Depression
  • Ataxia (loss of physical coordination)
  • Memory Loss
  • Loss of Cognition
  • Dystonia (muscle spasms)
  • Incontinence (bowel & urinary)
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5
Q

Why are Prion Diseases so dangerous?

A

• Inevitably fatal: no cures, only treatments to ease symptoms
• Most people with CJD will die within a year of the symptoms starting (often from
infection)

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6
Q

What are Physiological Characteristics of Prion Diseases?

A
  • Neuronal death leading to a spongiform appearance of the brain
  • Proliferation of astrocytes & microglia
  • Build up of amyloid plaques (protein aggregates)
  • Evidence of oxidative stress
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7
Q

Are Prion Diseases common?

A

No, they are very rare

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8
Q

What are the 3 Mechanisms by which Prion Diseases occur?

A
  • Sporadic (spontaneous)
  • Genetic (familial)
  • Acquired (infectious/ transmitted)
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9
Q

Sporadic (Spontaneous) occurrence of Prion Diseases

A
  • 85-90% of cases
  • Symptoms usually develop between the ages of 60 and 65
  • 1 -2 deaths per million people, 127 deaths in 2019
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10
Q

Genetic (Familial) occurrence of Prion Diseases

A
  • 10-15% of cases
  • Symptoms usually develop in early 50s
  • 1 per 9 million people, 5 deaths in 2019
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11
Q

Acquired (Infectious/Transmitted) occurrence of Prion Diseases

A
  • 2-5% of cases
  • V. rare
  • 1 death from iatrogenic infection in 2019
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12
Q

What part of the Brain is affected in Classic CJD?

A

Cerebral Cortex

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13
Q

What is the function of the Cerebral Cortex in the Brain?

A

Responsible for the higher-level processes of the human brain, including language, memory, reasoning, thought, learning, decision-making, emotion, intelligence and personality

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14
Q

What part of the Brain is affected in Fatal Familial Insomnia?

A

Thalamus

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15
Q

What is the function of the Thalamus in the Brain?

A

• Your thalamus is your body’s information relay station
• All information from your body’s senses (except smell) must be processed
through your thalamus before being sent to your brain’s cerebral cortex for
interpretation

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16
Q

What part of the Brain is affected in Kuru?

A

Cerebellum

17
Q

What is the function of the Cerebellum in the Brain?

A

Important for making postural adjustments in order to maintain balance

18
Q

What Prion Diseases affect the Brain Stem?

A
  • Scrapie
  • BSE
  • Chronic Wasting Disease
19
Q

What is the function of the Brain Stem in the Brain?

A

The brain stem is responsible for regulating most of the body’s automatic functions that are essential for life (regulation of heart rate, breathing, sleeping, and eating)

20
Q

Amyloid Plaques Structure

A
  • Comprised of protein
  • β-sheet rich
  • Proteins stack up to make fibrils (fibres)
  • Clump together to make a plaque
  • Prion protein (PrP)
21
Q

Routes of Infection for Prions

A
  • Ingestion

* Iatrogenic (relating to illness caused by medical examination or treatment)

22
Q

Types of Iatrogenic Infection for Prions

A
  • Corneal Grafts
  • Dura Mater Grafts
  • Human derived Growth Hormone Injection (hGH)
  • Experimental transmission in animal models
23
Q

How do Prions move from Mouth to Brain?

A
  • Prions detected by immune system
  • Resistant to proteolysis
  • Replicate in lymphoid tissue (especially follicular dendritic cells)
  • Enter central nervous system by nerves of the autonomic nervous system
24
Q

What is PrPC?

A

There is a normal cellular form of the prion protein PrPC

25
Q

PrPC vs PrPSc

A
  • PrPC & PrPSc share the same amino acid sequence
  • Coded by prnp gene on xsome 20 (human)
  • PrPC to PrPSc conversion is a key event in disease
26
Q

PrPC Structure & Characteristics (8)

A
  • GPI Anchored (Plasma Membrane)
  • Monomeric
  • Protease Sensitive
  • Binds Copper
  • Synaptic Location
  • 3 α–helices
  • 2 β-strands
  • NMR & X-ray
27
Q

PrPSc Structure & Characteristics (7)

A
  • Extracellular and Aggregated
  • Protease Resistant
  • No specific copper bound
  • Associated with Infectivity
  • Not easily Decontaminated
  • Secondary Structure
  • β-strand rich
28
Q

Mechanism of Neurodegeneration via Prions (4 Steps)

A
  • PrPSc is cytotoxic
  • Potential loss of antioxidant activity of PrPC
  • Apoptotic neurones cleared by microglia
  • Leave ‘gaps’ (sponge like) and protein plaques
29
Q

What causes initial formation of PrPSc in Sporadic Prion Diseases?

A
  • Definitive cause is uncertain
  • A spontaneous somatic mutation may have occurred in 1 of the Prnp genes
  • Normal PrPC protein may have spontaneously converted into the PrPSc form
  • Tends to be a susceptibility polymorphism in their Prnp genes
30
Q

Precautions for patients with/“at increased risk” of CJD undergoing Surgery (7)

A

• Perform the intervention in an operating theatre
• Schedule at the end of the list, to allow cleaning
• Involve the minimum number of personnel required
• Protective clothing should be worn (single use if possible)
• Single-use disposable surgical instruments and equipment should be used
where possible
• Equipment subsequently destroyed by incineration or sent to the instrument
store
• Effective tracking of reusable instruments should be in place, so that
instruments can be related to use on a particular patient

31
Q

Safety Measures to reduce any possible risk of spreading vCJD through Blood (5)

A

• Withdrawal of any blood components donated by anyone who develops vCJD
• Removing WBC from all blood used for transfusions (leucodepletion)
• Not accepting donations from people who may have received a blood
transfusion since 1980
• Promoting the appropriate use of blood, tissues & alternatives in the NHS
• Led to a reduced amount of blood transfused during and following surgery

32
Q

Potential Pharmaceutical Interventions for Prion Diseases (4)

A

1) Pnrp knockdown (reduces PrPC production)
2) Antibodies prevent prion conversion (PrPC to PrPSc conversion restricted)
3) Antibodies prevent prion aggregation (PrPSc aggregate formation prevented)
4) Compounds interfere with neurotoxicity (PrPC-mediated PrPSc toxicity)

Infection (21 decks)

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