Toxins and Prions Flashcards
Toxins are
diffusible molecules that can cause systemic havoc
Most toxic substances known
1⁄2 lb enough to kill all humankind
Most common neurotoxins
- Botulinum toxins – target motor neuron; inhibits exocytosis of SV (secretory vesicles, or synaptic vesicles)
- Tetanus toxins – target interneurons; inhibits exocytosis of SV
- Lethal toxin (anthrax produces)– potentially targets all neurons; affects cytoskeleton (cytoskeleton - in every cell in the body but also in neurons (moves SV))
___ are the most poisonous proteins known to humanity
Botulinum toxins
many toxins are produced by
Clostridia bacteria
Botulism is caused by
toxin, not living organism
Botulism is typically acquired from
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
Botulism symptoms
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
Botulinum toxin classes
7 different classes (A to G)
Botulinum toxin moa
Binds receptors on nerve terminals
Gets internalized and forms pores on vesicle
Leaves vesicles and cleaves fusion complex – inhibits release of acetylcholine
Botulinum toxin therapeutic uses
What is prion disease
prion - also agent, not living organism
miss folded protein causes others to misfold
Neurological disorders caused by pathogenic proteins
prions
Thought to be “slow viruses”, but resistant to inactivation methods
Lack any genetic material, single misfolded proteins (do not require any cellular processes)
Transmissible Spongiform Encephalopathy (TSE)
Absence of inflammatory response (why opathy and not iltis)
Neuronal death, astrocytic gliosis
Single, round empty spaces (in paranchyma)- like a sponge!
prion disease humans vs animals
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
Identified prion diseases
Characteristics of prion diseases
Long incubation times (~10 to >30 years)
Rapid progression after onset
No cure or treatment, invariably fatal
Definitive diagnosis only during autopsy
Discovery of human prion disease
Kuru
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
Kuru was transmitted by ____
most of the victims were ___
Kuru differences vs others
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
How do you get prion disease
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)
kuru type
Kuru was an acquired prion disease → created selective pressure on the Fore people → polymorphism on PRNP is protective
Properties of prions
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
Research on prion disease might impact our understanding of neurodegenerative disorders
prion diseases only develop if
PrPC → PrPSc is faster than PrPSc
clearance
same idea to amyloids accumulation → as we age, clearance slows down
how to remove prion from brain
Role of Pr in mediating neurotoxicity of misfolded protein aggregates
Microglia and astrocytes in prion-induced neurodegeneration
