Toxins and Prions

Question 1

Toxins are

Answer 1

diffusible molecules that can cause systemic havoc

Question 2

Most toxic substances known

Answer 2

1⁄2 lb enough to kill all humankind

Question 3

Most common neurotoxins

Answer 3

1. Botulinum toxins – target motor neuron; inhibits exocytosis of SV (secretory vesicles, or synaptic vesicles)
2. Tetanus toxins – target interneurons; inhibits exocytosis of SV
3. Lethal toxin (anthrax produces)– potentially targets all neurons; affects cytoskeleton (cytoskeleton - in every cell in the body but also in neurons (moves SV))

Question 4

___ are the most poisonous proteins known to humanity

Answer 4

Botulinum toxins

Question 5

many toxins are produced by

Answer 5

Clostridia bacteria

Question 6

Botulism is caused by

Answer 6

toxin, not living organism

Question 7

Botulism is typically acquired from

Answer 7

eating spoiled food

even if cook very well, cannot kill, maybe kill spore but cannot kill toxin

grow in anaerobic environment, acid and fermentation - kill bacteria but spores survive

wound - access via wound
food born - ~20% honey - very common spore

Question 8

Botulism symptoms

Answer 8

GI symptoms - flaccid paralysis (loose muscle tone, weakness, loose control, cannot control breathing, die)

Autocolonization possible (we all have Clostridium botulinum in gut) - may be asymptomatic, symptomatic, or neurological symptoms w/o GI problems

Question 9

Botulinum toxin classes

Answer 9

7 different classes (A to G)

Question 10

Botulinum toxin moa

Answer 10

Binds receptors on nerve terminals

Gets internalized and forms pores on vesicle

Leaves vesicles and cleaves fusion complex – inhibits release of acetylcholine

Question 11

Botulinum toxin therapeutic uses

Answer 11

Question 12

What is prion disease

Answer 12

prion - also agent, not living organism

miss folded protein causes others to misfold

Question 13

Neurological disorders caused by pathogenic proteins

Answer 13

prions

Thought to be “slow viruses”, but resistant to inactivation methods

Lack any genetic material, single misfolded proteins (do not require any cellular processes)

Question 14

Transmissible Spongiform Encephalopathy (TSE)

Answer 14

Absence of inflammatory response (why opathy and not iltis)

Neuronal death, astrocytic gliosis

Single, round empty spaces (in paranchyma)- like a sponge!

Question 15

prion disease humans vs animals

Answer 15

Rare in humans, invariably fatal and of rapid progression

More common in animals (livestock) - big impact on society - have to kill a lot of livestock

Question 16

Identified prion diseases

Answer 16

Question 17

Characteristics of prion diseases

Answer 17

Long incubation times (~10 to >30 years)

Rapid progression after onset

No cure or treatment, invariably fatal

Definitive diagnosis only during autopsy

Question 18

Discovery of human prion disease

Answer 18

Question 19

Kuru

Answer 19

translation - shivering/trembling
western - laughing disease

Originally thought to be a slow, unconventional virus

Odd disease restricted to the Fore people of Papua New Guinea

Question 20

Kuru was transmitted by ____

most of the victims were ___

Answer 20

Question 21

Kuru differences vs others

Answer 21

Lack of rapid progressive dementia seen in mad cow or CJD

displayed emotional changes → cerebellar ataxia → motor incapacitation → loss of speech → death within 1 year of onset

Differences in neurological symptoms, but very similar neuropathology
* Vacuolated neurons
* Excessive proliferation of astrocytes and microglia
* Appearance of amyloids (protein aggregates in a form that is insoluble)
* Plaques have abnormal prion protein (PrPSc)
* Minimal inflammation

Question 22

How do you get prion disease

Answer 22

3 types of prion disease based on mode of appearance
1. Sporadic - no idea how it happened - most cases are
2. Inherited - genetic
3. Acquired - mad cow

There is no direct person-to-person transmission

> 20 mutations have been identified that cause sporadic prion disease
(most common)

Question 23

kuru type

Answer 23

Kuru was an acquired prion disease → created selective pressure on the Fore people → polymorphism on PRNP is protective

Question 24

Properties of prions

Answer 24

Can go through filters that block bacteria/fungi/parasites - why thought slow virus

but Resistant to heat or UV light - should kill virus

No antibodies are generated - is its OWN protein

Can coerce normal molecules to change into
their abnormal shape
- Primarily α-helical to mostly β-sheets
- Maximum minimum of free energy

Possibly acting as a chaperone

Question 25

Research on prion disease might impact our understanding of neurodegenerative disorders

Answer 25

Question 26

prion diseases only develop if

Answer 26

PrPC → PrPSc is faster than PrPSc
clearance

same idea to amyloids accumulation → as we age, clearance slows down

Question 27

how to remove prion from brain

Answer 27

Question 28

Role of Pr in mediating neurotoxicity of misfolded protein aggregates

Answer 28

Question 29

Microglia and astrocytes in prion-induced neurodegeneration

Answer 29