Lecture 11 - SNAREs 2: Membrane fusion machinery in health & disease Flashcards
What do SNAREs drive?
SNAREs drive membrane fusion
What happens when the SNAREs end on sister complexes?
Taken apart via NSF and ATP hydrolysis
What processes occur to drive membrane fusion?
- nucleation
- zippering
- fusion-pore opening
- addition of NSF and SNAPs
- ATP hydrolysis
- budding
What happens when you inhibit membrane fusion?
The warming of flies leads to paralysis, however if you cool them back down, they are normal again. This is because the recycling of SNAREs after membrane fusion is allowed and the proteins becomes functional again in the permissive temperature.
What phenotype is seen with a mutation in the VAMP2 gene in mice?
die at birth, loss of synaptic transmission
What phenotype is seen with a mutation in the Syntaxin1A gene in mice?
No gross abnormalities. Subtle defects in synaptic transmission
What phenotype is seen with a mutation in the Synataxin1B gene in mice?
Die after birth. Reduced synaptic transmission
What phenotype is seen with a mutation in the SNAP25 gene in mice?
Die at birth. Loss of synaptic transmission
What disease arises from a mutation in VAMP in humans?
Neurodevelopmental disorder with hypotonia (reduced muscle tone) and autistic features with or without hyperkinetic movements
What disease arises from a mutation in SNAP25b in humans?
Neurodevelopmental disorder with seizures, intellectual disability, severe speech delay, and cerebellar ataxia (problems with movement)
What disease arises from a mutation in SNAP29 in humans?
Cerebral dysgenesis, neuropathy, ichthyosis, and CEDNIK syndrome (palmoplantar keratoderma syndrome)
What disease arises from a mutation in Syntaxin11 in humans?
Familial haemophagocytic lymphohistiocytisis (type4)
What type of mutation in VAMp2 causes a serious neurodevelopmental disorder?
Heterozygous mutations
What is the effect of S75P mutation?
slows the rate of liposome fusion
What is familial haemophagocytic lymphohistiocytosis?
- rare disease of the immune system
- predominantly effects infants
- over proliferation of T cells, natural killer cells, B cells & microphages
- life threatening condition (cytokine storm)
- caused by mutation in several different genes
- patients can die from infection die to defective killing in T-cells
T-cells kill infected cells by secreting cytotoxic granules
What does a mutation in syntaxin11 causes?
FHL4
- STX11 is a Q-SNARE that doesn’t have a transmembrane domain
- Patients with FHL4 have significantly reduced levels of STX11
- Loss of STX causes defective degranulation from cytotoxic T-cells by an unclear mechanism
What does a mutation in Munc18-2 cause?
Munc18-2 causes FHL5 and reduces the levels of STX11
What are clostridial neurotoxins?
Clostridial neurotoxins are a group of potent toxins produced by bacteria of the Clostridium genus. These toxins primarily affect the nervous system, leading to various types of neurological disorders.
The most well-known clostridial neurotoxins are produced by Clostridium botulinum and Clostridium tetani, which cause botulism and tetanus.
Describe the global trend of global tetanus deaths
Decrease from 300,000 (1990) to 50,000 (2017)
- mainly in under 5
What is the most common form of botulism?
Babies <6 months most susceptible - floppy baby syndrome
What are toxins dependent on?
Toxins are zinc dependent proteases
Are clostridial toxins taken up by all neurons?
They are only taken up neurons
Do clostridial neurotoxins cleave the same SNAREs?
no - different SNAREs
What is the difference between Tetanus & Botulinum toxins?
They have a similar mode of action but intoxicate different neurons
Describe Botulinum neurotoxins and their clinical uses
- Cosmetic uses
- Strabismus, blepharospasm, hemifacial spasm, cervical dystonia, axillary hyperhidrosis, over active bladder, GI tract disorders, sialorrhea, temporomandibular disorder and limb spasticity
- most products are based around Botulinum A and target SNAP25
- Treatment last for several months
- can’t make medicines based around tetanus as everybody is vaccinated against the toxin.
Due to their high efficacy, tolerance, longevity and satisfactory safety profile, BoNTs are now the most widely used therapeutic proteins
What is the Botulinum market currently valued at?
nearly 5 billion dollars
What can Botulinum A be used to treat?
Strabismus (cross-eyes)
What can Botulinum B be used to treat?
cervical dystonia
Summarise SNAREs 2
- disruption of SNARE function causes severe defects in neurotransmission and other physiological processes that require membrane fusion
- inherited SNARE based diseases are relatively rare
- botulinum and tetanus toxins have a conserved protein structure
- botulinum and tetanus toxins are potent inhibitors of SNARE function
- botulinum toxins can be used to treat neurological conditions associated with neuronal hyperactivity
