Please enable JavaScript.
Coggle requires JavaScript to display documents.
39 Molecular Cell Biology & Disease (3 Nov) (1- causes of disease…
39 Molecular Cell Biology & Disease (3 Nov)
1- causes of disease
there are many things that cause mutation, cause chemical change or infection
anything that causes mutation has the potential to effect cellular function
can occure from radiation
chemical mutegents
some of the organisms like to infect us
bacteria in our gut provide us with alot of nutrients
prions :star: proteanatous infectious particles
proteins that have folding deficit
they can become infectious causing mad caw diseas
heavy metals in periodic table
structural molecules of cells
problems with actin or microtubule
the regulation of cell signalling
ends up causing a huge amount of disease
quite easy to develop drugs that target cell signalling pathways
cell membrane transport
lot of diseases that can cause because cells are deficient on what they can take in and what they can get rid off
strucural molec. prob
Genetic
Prions
proteins that fold the wrong way
as oppose to develop a certain tertiary or quarternary structure
sometimes it can be infectious
parkinson : idea proteins that cant fold correctly and they become infectious within central nervous sys
chemical denaturation
anything that changes the protein function
overstimulation
hearing loss
overstimulation of hair cell
we over stimulate a K channel and that K channel will respond and start to close , you loose that frequency of hearing over time
Enzyme function problems
in 2 direction
2 tailed response
turning on and off enzymes
over active enzymes
blocking enzymes
mutation in the gene causes production of enzyme
absence of enzyme
causes a problem with methabolic pathway or digestive pathway
like lactose intolerant dont produce enough lactase
lactase is an enzyme that you secrete into your intestine and breaks up milk sugers
mutation in ezyme
no capable of digesting the sugars in milk
1 more item...
cell signalling
increase or decrease in the amount of neuro transmitter
chmical messengers that we have between cells
basis of mental illness
most depression
treatment: drugs that modulate how much of small molecules held in that synaps>>> the gap between 2 neurons in the brain
hormonal imbalance
gigantism, dwarfism, diabetes
problems inside the cell
cell signalling and reception
over active receptors like tyrosine kinases in breast cancer
intra cellular messengers
disregulating cyclic AMP= cholera
problems with channels
K channels or ca channels
problems with heart rithm like A rithm or disrithm are cause by ca channel or Na channel
deafness can be a mutation in K channel
how yeast recycle all of its organells
how we produce new mitochondrian and stop old one?
3-Autophagy –“self eating” :star:
how cells eat themselfs : in balance
to produce the new one
keeping cells happy by recycling old components
what happens? we have little membranmes that form inside a cell , membranes recognise damage cellular components , they wrap around them and they transport them to lysosome in things called autophagasome that fuse to the lysosome nad we get enzymatic degredation, principally mitochondria but there are other components within the cell as well
damage proteins, mitochondria
yeast has a big autophagosome called vacuol
it involves in cell size maintenance as well
he found 15 genes thet are essential for the formation of autophagosomes, recycling of cellular components of yeast
we are multicellular yeast
in terms od autophagy
all of the genes that are identified we have copies of that we use, this is a very old process
3 different mechanisms of autophagy
1- Macroautophagy
99% of important stuff
others are not important
what happens in Macroauthophagy?
Isolation membrane formed and it is called isolation membrane because it is a membrane that isolated from everything else
this then regognises by a lot of different mechanisms
this isolation complex recognises mitochondria that is in trouble or proteins that are in trouble, thing like prions that are inside the cell (proteins that are in trouble) they need to be chopped off and get read of
mt that is producing too many radicals can damage a cell
mt that are getting old and producing lots of oxidative stress need to be gotten rid of
isolation membrane pick up all the damage from the cell they inrapture them and taken them to the lysosome where they can be degraded , that is the entire process of Macro autophagy
2- Microautophagy :star: it can happen without isolation membrane
3- chaperone mediated autophagy :star:
mediated by other things called chaperone instead of isolation membrane
reason fo noble prize : the impact this can potentially have on disease and treatment of disease
when autophagy goes wrong you dont clear your MT or your old damaged proteins
mutation in a lot of those gene that isolated in yeast also occur in parkinson's disease and Alzheimer's disease
in Parkinson's disease we have a problem with a problem with a protein called alpha-synuclein, protein folds the wrong way and accumulate in plucks aggregates inside the cell
this normally get cleaved by autophagy but if that does NOT happen you will develop parkinson disease, toomuch of alpha-synulein aggregates will start to kill cell in a part of the brain (blask part) in the middle of the brain and controls movement
people with parkinson disease loose the ability to walk through doors
in instead, we have a protein called Beta- amyloid is effected
we form these tangles around our cells
if that is not cleared by autophagy you'll develope alzeimer disease
alzheimer disease is not confined in a bit in the middle
it tends to spraed out through the cortex
both parkinson and alzheimer disease have deficit in autophagy
we are producing this misfolded proteins and they are not cleared, not taken up by the autophagasom and if they were you'll be able to clear and prevent the pathology from happening
not just central nervouse system is effected by deficit in autophagy
most regions of your body have certain diseases and certain pathalogies that could be cleared by autophagy if we have efficient enough autophagy system
Cardiak hypertrophy
individual muscles in hearth become too big, they cant fit enough blood in ... you need to get blood into and out of hearth
no memrorisation needed
4- channel disease: Cystic Fibrosis
caused by a mutation in chloride channel
mouse model of cystic fibrosis
chloride channel sits in the plasma membrane and allows chloride to pass through regulated cl enflux from cells
what happens when a salt leaves a cell? water will also leave
when chloride leaving the cell it changes the osmotic potentials across the plasma membrame , water will follow chloride
cl channel regulates how much water has to leave the cell
it regulates the stickiness of mucosal lining everywhere
the mucosal lining of your lung and your gastrointestinal
the stickiness of the mucus on that is effectively regulated by the chloride channel and it can be opened and closed
open the cl channel to allow more water out of the cell
or close the chloride channel to keep the cl and water inside the cell
a mutation in cl channel : cystic fibrosis
can effect different parts of the body
it creates mucus that is the wrong consistency
its either too fluid can not trap things in it
or it is way too sticky and everything gets trapped in it
if we have the wrong consistency mucus lining in our gastotestinal track we cant absorb food - mal absobtion problems
problems with breathing because to breath correctly you have to have write consistency of mucus in your lungs
so they can pop open and allow air into them
we have a lot of mutation in Cystic Fibrosis Trans membrane conductance regulator CFTR :star:
CFTR is the chloride channel that cause cystic fibrosis
mutations that effect any part of the metabolism
mutations that cause no proteins to be formed
mut. that cause mutated proteins sent to the wrong place in the cell
mutation that produce disability so they get chopped off and taken
away
mutations that cause defective gating
means how quickly it opens and how quicly it closes
gating is done by second messenger
inside the cell these is a few second messengers that cause changes
one of them is called cyclic AMP
cyclic AMP is the molecule that causes Cystic Fibrosis = chloride channels to open and close
high cyclic AMP inside the cell
our chloride channel spring open
when cell signalling reduces that cell signalling inside our cells
our chloride channels close
stops our cells from loosing chloride and water
any signalling event thet increases the amount of Cyclic AMP inside of the cell opens the chloride channels >>> loose chloride and water
cAMP is raised by lots of thins, we call these things Secretatogogues :star:
literally anything that opens the chloride channel
1 more item...
CFTR mutations protect us from diarrhoea?`
the mutations that cause cystic fibrosis havent been eliminated from our genome
because if you have a mutation that stops you from being able to open chloride channels correctly you are protected from anything that causes you diarrhoea.
like cholera toxin action
cholera will infect your cells, release cholera toxin and that cholera toxin increases the amount of cyclic AMP in the cells
if you have a functioning cl channel, it will open up cl channels and you get diarrhoea
that cause a huge amount of death in the world
if you have a mutation in cl channel
then cholera toxin will have other effects but wont make you to loose 20 l of water per day
these channels are how Salmonella gets into your system
how Salmonella goes from gastrointestinal track into the body is through these channels
if cl channel held close, Salmonella can not enter your cells and will end up in the toilet
so we get a lot of protections by getting these minor mutations in the CFTR = Cystic fibrosis transmembrane conductance regulator
CTFRmutations –a potential lifesaver?
•
minor mutation is life saver
one mutation in CF is not life threathening and we can have protection from cholera and diarrhoea and Salmonella as well
this can effect evolution of disease interesting
mascular distrophies is the main mascular disease
one of them is 100% lethal called Duchenne muscular distrophy
if you have a mutation in the gene that causes Duchenne muscular distrophy
you will die between ages of 20 and 30
much better than what it used to be. it used to be before 20
treat with steroid drugs has prolonged life but it is universally lethal
lethal because of difragm and muscles that control your lungs
usually respiratory failure
spend about 10 to 15 years on a ventilator
death can occure because of lack of ventilation and inability to breath also cardiac failure because your hearth is a muscle as well functions by very similar mechanism
X linked recessive disease, only effect boys, because girls have 2 copies of
1 in 1000 boys are born with duchenne muscular distrophy
it is not passed on because on a wheelchair and ventilated you wont have kids
what that affects is a gene that provides Shock absobtion protein
muscle is a motor protein and structural protein and the motor protein called myosine and that motor protein pulls on that structural proteins on muscles
and when they pull they generate tention , if everything is vorking that tention will transmitted to tendence
and tendence transmit those tentions to bones
so skeletal muscles contract and that moves your bones
there are a lot of sock that needs to be absorbed to transmit that tention to bons
structural protein is actin which is microfilament
microfilaments get pulled on by motor protein myosine
actin transmit that force to transmembrane and it does that by protein called dystrophin
dystrophin gets mutated when we get muscular dystrophy
mutation in dystrophin causes it to not link up to the cell membrane
so we have contraction in our mucsles but the force is not being transmitted and over time your muscles tear themselves apart because the plasma membrane is not linked to contractile proteins they slip against eachopther and cause tears in muscles
tears in muscles result in damage and muscles are remarkebly good at repairing itself
1 more item...
2 types of mutation in dystrophin that cause totally different diseases
BMD Becker muscular distrophy
soar muscles throughout life not lethat
we dont insert a stop codon instead we get a mismatch where we get a change and we still get translation of the second bit
we get a semi functional protein being produced
causes loss of couple of the exons
we get a shorter protein but it got the front bit that attaches to the microfilaments and the back bit that attaches to plasma memb.
so shorter than the original, does not function quite as well but performing the same role
DMD Duchenne muscular distrophy is out of frame mutation
cause the insertion of stop signal at some poin in the gene
mutation stops translation
we end up with a protein that attaches perfectly well to the contractor part of the cell but it does not transmit that force to the plasma membrane and cells tear apart
normal non mutated dystrophin
has an end that attaches to the microfilament
and another end that attaches to plasma membrane
can we fix duchenne?
if we convert the mutations that causes duchenne muscular distrophy into sth that causes becker muscular distrophy
if we have some way of skipping (stop codon) mutation
change duchenne muscular distrophy to becker muscular distrophy
a drug is developed which is short piece of RNA which enables the ribosome to skip mutated point that causes the duchenne
drug called Eteplirsen
Eteplirsen will bind ribosome and when ribosome starts translating along it will skip the stop codon and translate the rest
1 more item...