Protein Misfolding And Disease 2

Question 0

Transmissible spongiform encephalopathies (TSEs)

Answer 0

Fatal, progressive, degenerative disease of the CNS
Infectious agent is prion (alternate form of normal brain protein)
In animals, characterized by incessant rubbing, wasting, loss of coordination, amyloid fibers in brain (scrapie, bovine SE, elk/deer wasting disease)
In humans, amyloid fibers (human Creutzfeldt-Jakob disease CJD)

Question 1

Protein conformational disease

Answer 1

Proteins adopt a misfolded structure that is toxic to cells, pathological

Question 2

Prions

Answer 2

Infectivity reduced by NaOH, sodium dodecyl sulfate, guanosine hydrochloride not irradiation or heat

Glycoproteins expressed in brain and many other organs

Question 3

Protein-only hypothesis

Answer 3

PrPc vs PrPsc (insoluble, protease insensitive, more b sheet
PrPsc molecules come together and bind via b sheet interaction, doesn’t dissociate easily->nucleus, addition of monomers is rapid

TSE has species barrier

Question 4

Potential therapies for TSEs

Answer 4

SiRNA silencing of PrPc-reduce about or PcP being synthesized

Stabilizing PrPc so it doesn’t convert into toxic species

Question 5

Alzheimer’s

Answer 5

Normal is AB40
Alzheimer’s plaques are amyloid fibers that are virtually all AB42
Produced by cleavage of APP by a, b, y secretases
AB42 interactions are mostly hydrophobic

Question 6

Alzheimer’s treatments

Answer 6

Modulating gamma-secretase activity (unspecific, may affect other pathways)
Antibodies that bind to AB

Question 7

Islet amyloid polypeptide (IAPP)

Answer 7

Cosecreted with insulin by Beta-cells islet of langerhans
Increase in insulin production leads to increased levels of IAPP
In late stages of diabetes, large scale apoptosis causes beta-cell crisis
Helical tendencies, Hydrophobic face bind lipid bilayers which accelerate rate of amyloid fibril assembly
Possibly pore formation in membrane from oligomers of IAPP

Question 8

Peptide inhibitors of AB and IAPP fibril formation

Answer 8

Fibrils are beta sheets, grow by forming side chain-side chain interactions and peptide-peptide H bonds
Inhibitory peptides cap the beta sheets (methylated peptide nitrogen son growing face so H bonds can’t form) to prevent them from growing