Holy Final Questions Flashcards
What are the two types of protein aggregates seen in Alzheimer’s disease?
Neurofibrillary tangles and beta amyloid plaques
what causes te formation of neurofibrillary tangles in AD?
The protein Tua is usually associated with microtubules and helps the microtubules interact with other cell components.
However, in AD, the tau proteins are hyperphosphorylated, which leads to the aggreagation of the tau proteins into neurofibrillary tangles within cells
What leads to the aggregation of amyloid plaques?
Amyloid precursor protein is a transmembrane protein that can undergo a series of proteyolytic cleave by secretase enzymes which come in three flavors: alpha, beta, and gamma.
The alpha secretase is the good one - it cleaves APP in such a way that id does not become aggreagated.
If it is not cleaved by alpha secretase, APP becomes a substrate for beta secretase followed by gamma secretase
These cleave the APP in such a way that releases an alpha beta peptide.
This alpha beta peptide can then clump into oligomers, which then aggregate into amyloid plaques extracellularly.
Mutations in the APP gene tend to block the activity of the alpha secretase and enable cleavage by beta and gamma secretase
How does the beta amyloid plaque cause the neurological symptoms associated with AD?
The soluble oligomers of amyloid protein impair synaptic function between neurons.
The oliomers may aggregate into insoluble beta sheets amyloid ribilrs which can trigger a local inflammatory response.
Over time, the subsequetnt oxidative stress and biochemical changes lead to neuronal death
Where do the different secretases act on APP in the cell?
APP mature through the constitutive secretory pathway and are continually cycled between the plasma membrane and endosomes.
The alpha secretase is present on the plasma membrane.
The APP will then cycle back throguh to the endosomes which is where the beta and gamma secretases are located.
then the badly cleaved PRPP cycles back to the plasma membrane where it can be exocytosed and generate extracellular plaques
How is the TACE enzyme related to AD and prion diseases?
Tace triggers alpha secretase to cleave both APP and PrPc. This is the good thing - we want this to happen.
Under pathological conditions, however, the PrPc will act as a scaffold to help oligomerize the beta amyloid released by cleavage by the beta and gamma secretases.
This promotes Alzheimers disease.
There is then a positive feedback loop because the association of PrPc and beta amyloid activates a signalling pathway that inhibits TACE.
Describe the CFTR.
It’s a member of the ABC transporter groups of proteins that activately transports Cl- out of the cell
It’s mutated in cystic fibrosis
it’s autosomal recessive and quite common in caucasians
It results in thickened mucus particularly in the lung, GI, and reproductive tracts
What are the 5 potential types of alterations associated with cystic fibrosis mutations?
- block synthesis of the receptor competely
- Block the processing of the receptor so it never make sit to the membrane and is broken down in the proteosome instead (this is most common)
- BLock in the regulation of the transporter
- Alter the conductance - so lower its functioning
- Reduced synthesis - so you might get some protein, but not enough
What exactly does the LDLR bind to?
It binds to the ApoB100 on the LDL particle.
What happens to the LDLR after it brings in an LDL?
It’s recycled in a vesicle and brought back tot he plasma membrane
What coating protein is associated with the endocytosis of LDL through the receptor?
clathrin - it coats the pits that pinch in and are endocytosed
What does dystrophin do in a healthy cell?
It is a long linking proteins that links the actin with a complex of integral membrane proteins.
It strengthens the muscle cells
What are the three different types of epidermolysis bullosa?
Simplex
junctional
dystrophic
What does epidermolysis bullosa simplex cause blistering? What protein does it target?
It’s the most common and mildest - symptoms usually begin around birth or infancy. You get blisterin on palms and soles of feet mainly.
It is an autosomal dominant disease.
It involves mutations in keratins.
The separation occurs within the epidermis itself.
What happens in junctional epidermolysis bullosa?
This one is severe and becomes apparent at birth.
It involves mutation in proteins associated with hemidesmosomes (laminin, collagen 17, integrin)
This one is autosomal recessive.
The blistering occurs at the junction between the epidermis and the dermis (because it affects the hemidesosomes connecting the epithelial cells to the basal lamina)
