Protein Misfolding Diseases

Question 1

What things could cause misfolding?

Answer 1

Mutations, Post-translational mod, spontaneous processes

Question 2

CF gene and what it codes for

Answer 2

CFTR for transport of chloride ions through membrane

Question 3

Mutation of CF

Answer 3

Delta-F508 (phenylalanine) folding incorrectly and not transported to membrane
Phenylalanine is missing

Question 4

Aggregation mechanism

Answer 4

Residues that like to associate are sufficiently exposed so that molecules have a reasonable probablility to sticking to one another

Question 5

Amyloidoses caused by

Answer 5

Soluble proteins

Question 6

Amyloidoses examples

Answer 6

Alz, Parks, Hunt, T2DM, prion, familial

Question 7

Neurodegenrative amyloidoses vs. familial amyloidoses

Answer 7

Neuro - smaller deposits

Familial - larger

Question 8

Transthyretin Amyloidosis…other name, inheritance, cause

Answer 8

Familial amyloid polyneuropathy
Autosomal dominant
Mutation (Val30Met) of transthyretin gene
Need liver transplant

Question 9

Transthyretin structure

Answer 9

Homotetramer

Question 10

All amyloid like deposits are

Answer 10

B-sheet rich

Question 11

Remainder of protein besides B-sheet

Answer 11

Decorates outside of fibril

Other proteins stick as well

Question 12

Huntington’s Dz…inheritance, symptoms

Answer 12

Autosomal dom neurodegen disorder

Motor impairment, cog defects, personaliy changes

Question 13

HD causes

Answer 13

Massive neuronal death and cell loss due to proteinaceous deposits in neural tissue

Question 14

HD gene and mutation that occurs

Answer 14

Huntingtin
Has region with many glutamine-encoding codons (CAG) polyglutamine
In HD, glutamine codon is longer

Question 15

Why does polyglutamine form amyloid-like structures?

Answer 15

Gln side chain can form H bonds with self like protein backbone
Have 2 layers

Question 16

HD age of onset and cutoff

Answer 16

Longer polyglutamine sequence=earlier

32

Question 17

AZ dz forms and what it is characterized by

Answer 17

Familial and sporadic (most common)

Plaques and tangles

Question 18

Plaques from

Answer 18

Abeta

Question 19

Tangles from

Answer 19

Tau

Question 20

Abeta cleavage normal and in Az

Answer 20

Normal - alpha, gamma
Alz - beta, gamma
Forms longer peptide that can aggregate

Question 21

Abeta formed by cleavage of

Answer 21

APP - amyloid precursor protein

Question 22

Abeta peptide

Answer 22

Hydrophobic and can form hair-pin like structures
Abeta1-40 most common
Longer is worse (42)

Question 23

Abeta peptides form what prior to fibril

Answer 23

Hairpin monomer, beta sheet oligomer, protofibril

Thought that smaller may be neurotoxic

Question 24

Tau is

Answer 24

Microtubule binding protein

Question 25

What happens to tau in alz

Answer 25

Hyperphosphorylated and aggregates…NOT driven by hydrophobicity

Question 26

Other tauopathies

Answer 26

Frontotemporal dementia - no Abeta aggregates

Question 27

Which comes first, A beta or tau

Answer 27

Abeta…could cause hyperphosphorylation by recruiting kinases…don’t know