Proteinopathies

Question 1

non-covantent interactions that dictate and stabilize protein structures

Answer 1

electrostatic interactions, h-bonding, dipole, hydrophobic interactions

Question 2

role of chaperones

Answer 2

prevent protein misfiling by helping proteins overcome kinetic energy barriers to forming native state/avoid getting stuck in local minima

Question 3

Why do incompletely folded proteins form aggregates?

Answer 3

they have hydrophobic residues on their surface and can easily associate with one another

Question 4

chaperonins

Answer 4

large, cylindrical complexes that have a central compartment for a single protein chain to fold without possibility of aggregation

Question 5

Molecular basis of Alzheimer’s disease

Answer 5

extracellular amyloid-B (AB) deposits and intracellular neurofibrillary tangles of tau proteins - triggered by phosphorylation of tau in neurons by AB

Question 6

amyloid-B (AB)

Answer 6

proteolytic fragments of amyloid precursor protein (APP) formed by cleavage of APP by B-secretase followed by y-secretase.

toxic as small oligomers, less toxic as long fibrils visible as plaques

Question 7

differences between hyperphosphorylated and normal tau protein

Answer 7

normal tau is soluble and promotes assembly of microtubules

hyperphosphorylated tau is insoluble, does not have affinity for microtubules, and aggregates into paired helical filament structures.

Question 8

mutations responsible for familial AD

Answer 8

overproduction of AB due to mutations the genes for APP or y-secretase

Question 9

Why do adults with Down syndrome have higher rates of early-onset AD?

Answer 9

APP is on chromosome 21 - Down syndrome = extra chromosome 21 = increased expression of APP

Question 10

APOE genotypes and risk

Answer 10

ApoE4 has Arg at both positions (112, 158) and increases risk for AD (more so for individuals with E4/E4 than E3/E4, E2/E4).

ApoE3 is the neutral ApoE genotype

Question 11

Molecular basis of Parkinson’s disease

Answer 11

accumulation of neurofibrillary tangles made of polymers of a-synuclein protein, which is in neural tissue at the presynaptic terminals.

called levy bodies

a-synuclein known to interact with tau, and also forms amyloid filaments

Question 12

molecular basis of Huntington’s disease

Answer 12

CAG repeat expansion for polyglutamine sequences near Huntington protein.

amyloid-like fibrils that contain B-sheet structures, with small aggregates being more toxic

Question 13

Huntingtons disease and genetic likelihood of developing it

Answer 13

autosomal dominant

HTT gene with fewer than 35 CAG repeats do not develop disease.

HTT gene with 40+ CAG repeats develop disease as they age.

longer repeats = increased severity and earlier onset

exhibits anticipation

Question 14

prions

Answer 14

proteins acting as infectious agents without DNA/RNA, which cause transmissible spongiform encephalopathies - neurogenerative disorders

Question 15

molecular basis of prion diseases

Answer 15

deposits of insoluble, protease-resistant PrP that aggregate into fibrils - mostly organized into B-sheets rather than a-helices of normal PrP protein

Question 16

genetic mutations that are associated with inherited prions disease & somatic prion disease are located on which gene?

Answer 16

PRNP - which encodes for prion protein

Question 17

How is Creutzfeldt-Jakob disease transmitted?

Answer 17

inherited, sporadic, infectious, or iatrogenic (from corneal transplants, surgical instruments, formerly from growth hormone derived from cadavers)

Question 18

How can prions that cause Creutzfeldt-Jakob disease be removed from surgical instruments?

Answer 18

sterilize with alkali rather than heat

Question 19

Genetic mutations associated with Parkinsons disease

Answer 19

Parkin, UCHL1 - involved in ubiquitin degradation of misfiled proteins.

SNCA - gene coding for a-synuclein - cause misfiling or over-expression of a-synuclein

Question 20

what is the most important driver of protein folding?

Answer 20

hydrophobic effect - folding a protein so that the hydrophobic sidechains are clustered together in the interior decreases the number of water molecules in contact with the hydrocarbon and results in a net increase in the entropy of the water - decrease in total free energy

Question 21

Why are prion proteins resistant to proteases, heat, and detergent?

Answer 21

misfiled PrP protein is highly stablehand resistant to protein unfolding. heat and detergent cannot unfold them, and proteases cannot access the peptide bonds to cleave them due to PrP protein’s rigidity

Question 22

What is the only way to destroy a prion?

Answer 22

alter chemical structure by hydrolyzing peptide bonds with a strong base or oxidizing its functional groups with a strong oxidant

Question 23

How would a reduced expression of chaperones increase the risk of AD?

Answer 23

chaperones interact with misfiled proteins until they refold or are degraded - because AB is difficult to refold or degrade, chaperones get tied up with them and if there are fewer chaperones to begin with, AB would be allowed to accumulate.