College aantekeningen
Colleges Neurodegenerative Diseases
- Instelling
- Rijksuniversiteit Groningen (RuG)
samenvatting van de colleges over neurodegeneratieve ziekten
[Meer zien]Voorbeeld 4 van de 67 pagina's
Voorbeeld 4 van de 67 pagina's
In winkelwagengesponsord bericht van onze partner
Verkoper
VolgenVoorbeeld van de inhoud
Neurodegenerative DiseasesIntroduction and Neurotoxicity College 1 1-9-20
Neurotoxins and molecular mechanisms of neuronal cell death and survival.
Neurotoxins:
Two mechanisms:
1. Disturbing neuronal functions
2. Induction of neuronal cell death
3. Molecular mechanisms of neuronal cell death:
Stroke
Alzheimer
Parkinson
Tetanus (Clostridium tetani)
We have been in contact with this bacteria as a newborn child, and every
twelve years we need to refresh that. Tetanus is produced by the red guys,
spore forming anaerobic bacteria and it is a protein toxin. It is a really big
protein. These guys can only survive because they form spores (blue). When
they form a normal bacterial body, they produce this tetanus toxin which is 11-
12% of the wet weight of the bacteria. We need a very small amount of this to
make you sick. They cannot survive in our atmosphere because they are
anaerobic. It is very likely that we can get it via a wound in the garden. The
bacteria sporulate and produce tetanus toxin. Most of the time people have a curved back, which is
called distotonus, a face with all muscles contracted. All these symptoms are specific of tetanus.
Complete contraction of muscles. The interesting thing is that there is another toxin that is a
homolog and this is even more dangerous.
Botulism (Clostridium botulinum)
It is quite similar to tetanus in structure, it has a lot of similarities. It causes the absolute opposite
effect. It is an anaerobic bacteria we find mainly in food, for example sausages or canned food. Once
you swallow this toxin, all the covering proteins are removed in the gut. The naked botulism toxin
can get in your blood stream and gets to the muscles where it leads to a complete relaxation of the
muscles. It is used in botox to relax muscles and prevent wrinkles. Botulism toxin is the most toxic
compound so this is really dangerous. 6 picogram is enough to kill a mouse so therefore you will get
very diluted botulism toxin. Tetanus toxin cannot be used.
Tetanus induces a strong contraction of skeletal muscles leading to painful spasms
Botulism leas to a flaccid paralysis and prevents breathing
They exhibit the opposite effect because they attach to different places in the body. You
cannot contract you muscles anymore with botulism and you cannot breathe anymore. With
tetanus you will get painful contractions, leading to painful spasms.
Bot toxins belong to the same family of protein toxins and exhibit strong homologies. Both
toxins are produced by anaerobe spore forming bacillae of the genus Clostridium: C. tetani
and C. botulinum
,Tetanus toxin is encoded on a plasmid with 75.000 basepairs, the
tetanus gene is the red part in the plasmid. It is coding for a
neurotoxin consisting of a light chain in red, a translocation domain
and a ganglioside binding domain. The structure is the same in
botulism. They have a sink binding which is a protease.
However the way they act and the place where they act is via the ganglioside binding domain. They
bind to gangliosides and to multiple receptors, where the binding affinity is very high. You cannot
wash away the toxin once it is bound to the receptor.
Both toxins are taken up by the body but in different ways. In the case of tetanus it is taken up into
the central nervous system via the peripheral nervous system. Botulism is taken up in the blood and
goes to the neuromuscular endplate and thus acts on the periphery where tetanus acts centrally (!!).
Tetanus is transported into the central nervous system. Once tetanus toxin is taken up and reaches
its final target it releases and fuses with endosomes and lysosomes which are acidic. And this acidic
surrounding leads to the translocation into the membrane where it forms a pore and releases the
light chain into the cytosol and the proteases act on the target molecules. Tetanus acts on the
blockage of gabanergic an glycine neurons in the brain. Botiulism toxin acts on the blockage of the
release of acetylcholine at the muscular endplate so there is no stimulation of the muscles
possible.
Interneurons and extensors
Tetanus toxin inhibits the release of interneurons. This is always inhibitory. These interneurons are
there to moderate our neuronal function. What happens when you cut off the interneurons, typical
tetanus patient gets spasms because all the muscles are contracted. Not all muscles are there for
movement but also for breath and keeping up the bodytonus. Our back muscles are usually much
stronger, therefore there is back bending and they can even break their own back. They put the
patients into a dark room where they are sedated and no noise, they give them muscle relaxants and
they will be there for a long time until the toxin is removed from the body. The afferent input always
lead to an motor output. Tetanus acts on the interneurons and botulism acts on extensors. Tetanus
acts on GABAergic and glycinergic and botulism blocks acetylcholine.
Vesicles
How do they do it? Once the vesicle with neurotransmitter is empty, they get recycled and reloaded
with neurotransmitter via ATP. And the vesicles will be filled and released again in the synapse.
Glutamate transmitters and NMDA are associated with a huge amount of other signalling proteins
and receptors. These areas are typical for excitatory neurons. There are different steps of
mobilization of these vesicles and this is done via calcium. Calcium input leads to the fusion of the
vesicle, that’s where botulism and tetanus are acting. Because there is a number of protein involved
in the processes. They are regulating all these steps.
,The light chain alone is sufficient to inhibit the neurotransmitter release. This is the major culprit in
both tetanus and botulism. These are the proteases that cleave proteins that fuse the vesicles to the
plasma membrane. There are a number of proteins that play a role and can inhibit this process.
Synaptobrevin: cleaved by botulinum toxin B, D, F & G, and tetanus toxin
Syntaxin: cleaved by Botulinum toxin C1
Snap- 25: cleaved by botulinum toxins A & E
They inhibit the fusion of the vesicle with the plasma membrane through distortion of the
SNARE proteins inhibiting the use of the neurotransmitters in that vesicle.
Stroke is not considered as a neurodegenerative disease but mechanisms causing the stroke are.
These also play a role in alzeimers parkinson and MS
Stroke
Is usually an ischemic stroke where a blood vessel is clotted in the brain, there is direct necrotic
tissue which is called the core. The surrounding area, penumbra, is characterised as apoptotic cell
death. There are several ways for apoptotic cell death, there are different mechanisms. Many people
recover very well but that depends on the area that is affected. Some areas are much more
important for our survival, these are closer to the brain stem, and can lead to disabilities. Depending
where you have your stroke the outcome can be more or less severe. What happens in a stroke can
be understood as where the brain consumes most of the energy in our body. 20-25% goes to the 1,5
kg aka the brain. Therefore we need a lot of glucose and oxygen and a lot of ATP which is produced
by the mitochondria. Even if we are resting the brain needs a lot of energy for maintaining the
electrical current. Fluorinated glucose is used for a tracer of brain activity, where it is highest more
glucose is consumed. Our brain needs lots of energy, the higher the activity the higher the energy.
Therefore there are a lot of blood vessels present. If you have a clotted vesicle a brain area does not
get enough energy and oxygen and the cells will dye in a short period of time.
Core: necrosis
Penumbra: apoptosis
, Excitotoxicity
In minutes or hours you have ischemia. Excitotoxicity is a expression that characterised where
glutamated NMDA and AMPA receptors are overstimulated. This leads to a toxic effect of these cells.
The typical sign of necrosis is that it gets destroyed and the inside goes to the outside including lots
of glutamate and overstimulates receptors causing excitotoxicity. These receptors controls the
calcium influx which will get higher leading to pumping out everything the cells have. This calcium
also leads to an disturbance of mitochondrial function which leads to less ATP and more ROS.
Inflammation
The TNF receptor family are known to induce extrinsic apoptotic processes, these are membrane
receptors and they cause different forms of apoptosis. If the complex IIb necrosome is used and also
the RIP, necroptosis takes place and after that inflammation.
There is not a lot of time to treat a stroke, four hours. Then they can resolve the stroke otherwise
you will have a permanent cell damage. If you wait to long the chance on repairing anything will get
lower.
Apoptosis
The induction of apoptosis is always a balance of neuronal survival and cell death. Why is apoptosis
an protective mechanism. It prevents the spreading of glutamatic substances. Therefore apoptosis
prevents the exitotoxicity and keeps it to a restricted sustained area. It is not an all or nothing
process, there are processes in between. A cell is an autonomous organism and gives signals to its
surroundings. Only in extreme events apoptosis occurs, and only in very negative surroundings it
enters necrosis. Depicted nuclei are a sign of apoptosis caused by glutamate. Even at a high
concentration and after a long time of exposure some cells survive, these are the cells that do not
have the glutamate receptors. Caspases are necessary for the induction of apoptosis. If you block this
via ZVAD, then the apoptosis will not happen. It is an process that is mainly activated from the inside
from the mitochondria. Overstimulation of calcium ROS damage neurons glutamate induce
overstimulation of these neurons.
TNF receptors induce extrinsic apoptosis and if RIP is present it leads to necroptosis DAMPs
activating inflammation. Necroptosis is apoptosis with inflammation processes.
TNFR2 has a stabilization effect on the mitochondrial function
Voordelen van het kopen van samenvattingen bij Stuvia op een rij:
Verzekerd van kwaliteit door reviews
Stuvia-klanten hebben meer dan 700.000 samenvattingen beoordeeld. Zo weet je zeker dat je de beste documenten koopt!
Snel en makkelijk kopen
Je betaalt supersnel en eenmalig met iDeal, creditcard of Stuvia-tegoed voor de samenvatting. Zonder lidmaatschap.
Focus op de essentie
Samenvattingen worden geschreven voor en door anderen. Daarom zijn de samenvattingen altijd betrouwbaar en actueel. Zo kom je snel tot de kern!
Veelgestelde vragen
Wat krijg ik als ik dit document koop?
Je krijgt een PDF, die direct beschikbaar is na je aankoop. Het gekochte document is altijd, overal en oneindig toegankelijk via je profiel.
Tevredenheidsgarantie: hoe werkt dat?
Onze tevredenheidsgarantie zorgt ervoor dat je altijd een studiedocument vindt dat goed bij je past. Je vult een formulier in en onze klantenservice regelt de rest.
Van wie koop ik deze samenvatting?
Stuvia is een marktplaats, je koop dit document dus niet van ons, maar van verkoper isapoortman. Stuvia faciliteert de betaling aan de verkoper.
Zit ik meteen vast aan een abonnement?
Nee, je koopt alleen deze samenvatting voor €7,49. Je zit daarna nergens aan vast.
Is Stuvia te vertrouwen?
4,6 sterren op Google & Trustpilot (+1000 reviews)
Afgelopen 30 dagen zijn er 64438 samenvattingen verkocht
Opgericht in 2010, al 14 jaar dé plek om samenvattingen te kopen