Protein Misfolding Diseases Flashcards
What things could cause misfolding?
Mutations, Post-translational mod, spontaneous processes
CF gene and what it codes for
CFTR for transport of chloride ions through membrane
Mutation of CF
Delta-F508 (phenylalanine) folding incorrectly and not transported to membrane
Phenylalanine is missing
Aggregation mechanism
Residues that like to associate are sufficiently exposed so that molecules have a reasonable probablility to sticking to one another
Amyloidoses caused by
Soluble proteins
Amyloidoses examples
Alz, Parks, Hunt, T2DM, prion, familial
Neurodegenrative amyloidoses vs. familial amyloidoses
Neuro - smaller deposits
Familial - larger
Transthyretin Amyloidosis…other name, inheritance, cause
Familial amyloid polyneuropathy
Autosomal dominant
Mutation (Val30Met) of transthyretin gene
Need liver transplant
Transthyretin structure
Homotetramer
All amyloid like deposits are
B-sheet rich
Remainder of protein besides B-sheet
Decorates outside of fibril
Other proteins stick as well
Huntington’s Dz…inheritance, symptoms
Autosomal dom neurodegen disorder
Motor impairment, cog defects, personaliy changes
HD causes
Massive neuronal death and cell loss due to proteinaceous deposits in neural tissue
HD gene and mutation that occurs
Huntingtin
Has region with many glutamine-encoding codons (CAG) polyglutamine
In HD, glutamine codon is longer
Why does polyglutamine form amyloid-like structures?
Gln side chain can form H bonds with self like protein backbone
Have 2 layers
HD age of onset and cutoff
Longer polyglutamine sequence=earlier
32
AZ dz forms and what it is characterized by
Familial and sporadic (most common)
Plaques and tangles
Plaques from
Abeta
Tangles from
Tau
Abeta cleavage normal and in Az
Normal - alpha, gamma
Alz - beta, gamma
Forms longer peptide that can aggregate
Abeta formed by cleavage of
APP - amyloid precursor protein
Abeta peptide
Hydrophobic and can form hair-pin like structures
Abeta1-40 most common
Longer is worse (42)
Abeta peptides form what prior to fibril
Hairpin monomer, beta sheet oligomer, protofibril
Thought that smaller may be neurotoxic
Tau is
Microtubule binding protein
What happens to tau in alz
Hyperphosphorylated and aggregates…NOT driven by hydrophobicity
Other tauopathies
Frontotemporal dementia - no Abeta aggregates
Which comes first, A beta or tau
Abeta…could cause hyperphosphorylation by recruiting kinases…don’t know
