Amyloidosis Flashcards
Diseases involving amyloid proteins.
Creutzfeldt Jakob disease
Bovine Spongiform Enceophalopaty,
in humans causes variant CJD.
Kuru, transmitted from brain cannibalism
ALzheimers
Parkinson’s
Huntingtons
Gerstmann Ataxia
Fatal Familial Insomnia
Levinthals paradox
It would take longer time than the universe has existed for a protein of significant length to fall into its most thermodynamically stable state by random trial and error.
Chaperones are therefore a required/universal part of protein folding, it is a cooperative process with folding occurring actively in segments as the protein is transcribed
What are the functions of chaperones
1) To aid in the correct folding
2) to prevent formation of aggregates and amyloid fibrils.
What are some human chaperone proteins
HSPs
HSP40, HSP70, HSP 90
What are the proteins responsible for protein ubiquitinylation
E1 E2 E3
E1 enzyme along with ATP binds to the ubiquitin protein.
The E1 enzyme then passes the ubiquitin protein to a second protein, called Ubiquitin carrier or conjugation protein (E2).
The E2 protein complexes with an Ubiquitin protein ligase (E3).
E3 ubiquitinylates the target.
What are the proteins responsible for targeting proteins to autolysosomes?
p62
NBR1
p61, ubiquitin binding protein p62, sequestosome
NBR1, Autophagy cargo receptor protein
What tertiary structure change is characteristic for amyloids
Proteins that contain many alpha helices in their properly folded form,
Convert to parallel beta-pleated sheets.
Overlap one another and form long amyloid fibrils
Why are they called amyloid deposits?
They stain similarly to starch - aka amylose - so researchers called them all amyloid before they knew they were proteins.
What special stain is unique for amyloid
Congo red
They show red-green birefringence under visible-polarized light respectively
Types of amyloidosis (systemic)
AL, AA, Abeta, TTR, Beta2-microglobulin
AL: Amyloid light chain, from Ig light chain protein
AA: Amyloid associated. From Serum Amyloid A protein. SAA acute phase protein.
Abeta amyloid: from amyloid beta protein found in alzheimer’s disease. Generated by cleavage from the synaptic membrane protein APP, amyloid precursor protein.
In extracellular plaques in the brain and also deposited in CNS vessels.
ATTR: Transthyretin.
Serum TRANSport protein for THYRoxine and RETINol.
Mutated TTR proteins cause familial amyloidosis with polyneuorpathies, and cardiac deposits
Beta-2 microglobulin: Component of the MHC class 1 protein. A normal serum protein that causes amyloidosis in long term dialysis patients. It is not removed by dialysis and accumulates.
Cause and symptoms of primary amyloidosis
It is the AL class
Caused by hypersecretory clone of plasma cells causing Ig Light chain secretion
Bence Jones proteins in blood and urine.
Microinfarcts and obstruction of the kidney tubules. Eventual renal failure.
Macroglossia, gigantic tongue
Cause and symptoms of secondary amyloidosis
AA class Caused by chronic inflammatory disorders, constant low grade liver APR activation, chronic SAA secretion.
Affects the kidney again
Also causes Rheumatoid arthritis due to immune complex deposition.
ATTR cause and symptoms
Point mutation causing transthyretin amyloid formation.
Familial disease
Or seen in elderly as senile ATTR.
Causes polyneuropathy
Restrictive cardiomyopathy from deposits.
Diastolic failure of the ventricles, and dilation of the atria.
Types of localized amyloidosis
Neuropathies
Cardiovascular
Skin, lichens.
What gene/protein mutations are is causative for both Fatal Familial Insomnia and Gerschmann Ataxia?
PrP protein, Major Prion Protein
From the PRNP gene. PRioN Protein.
The PrP protein in its prion form is also the causative infectious agent in Creutzfeld Jakob disease, Kuru, and BSE
