Role of Protein Aggregation in NDD Flashcards
(37 cards)
What contributes to Protein Aggregation?
- Protein modification o Mutations of genes encoding the aggregating protein o Post-translational modifications ♣ Phosphorylation ♣ Nitration ♣ Etc. o Cellular stresses ♣ Oxidative damage - Inappropriate interactions - Increased protein levels - Abnormal protein levels - Abnormal protein degradation pathways - Altered trafficking
What are the disease causing mutations for PD?
SNCA - A30P, A53T, E46K, H50Q
What are the disease causing mutations for AD?
APP - K670N, A692G, I176V
What are the disease causing mutations for Prion disease?
PRNP - P120L, E200K
What are the disease causing mutations in HD?
HTT - PolQ >36
What are the disease causing mutations in FTD?
MAPT - P301L
What encourages aggregation?
Phosphorylation at residues serine, threonin and tyrosine, this makes the residue “bulkier” and its charge could potentially disrupt typically protein fold
What encourages Asyn aggregation?
Serine-129 phosphorylation
What encourages aggregation of tau?
Hyperphosphorylation of Tau fibrils
What is oxidative stress?
Oxidative stress is where there is an increase in species that can lead to oxidation, most commonly reactive oxygen species (ROS)
What are the pathways that can generate ROS?
o Mitochondrial Respiratory Chain (MRC)
♣ Main cellular site of superoxide formation, marked increased when MRC function disabled
o Activated phagocytic cells
♣ Neutrophils, macrophages, microglia, lead to release of O2, hydrogen peroxide and nitric oxide
o Auto-oxidation reactions
♣ Some biological molecules oxidise in the presence of O2 to form O2-
o Catalysed by transition metals:
♣ Fe2+ - Fe3+
♣ Cu+ - Cu2+
o Metabolic pathways
♣ Dopamine + O2 + 2H2O dihydrophenyl acetic acid + hydrogen peroxide + ammonia
o ER
♣ Cytochrome P540 system involved in detoxification, catalyses hydroxylation reactions involves superoxide generation
What are indicators of OX stress in PD?
- Increased levels of free iron
- Decreased levels of reduced glutathione
- Decreased levels of polyunsaturated fats
- Decreased Cu/Zn Super oxide dismutase activity
What are indicators of OX stress in AD?
- Increased levels of DNA damage
- Increased levels of Protein carbonyls and nitrotyrosine
- Increased levels of lipid peroxidation
- Increased iron and copper
What are the indicators of OX stress in HD?
- Few indicators
- Mitochondrial dsyfunction
- Excitotoxicity which is thought to play a role in encouraging OX stress
What are the indicators of OX stress in ALS?
- Excitoxicity
- Neuroinflammation is thought to encourage the process
- Mutations change the specificity of SOD1
What is the effect of OX stress on DNA?
- OH forms an adduct with guanine
- Can lead to dsBreaks
- Can deaminate adenine - hypoxyanthinine
- Changes the interactions with associated proteins, ultimately altering DNA replication signals, could silence or constituitively activate genes
What is the effect on lipids?
- OH can extract a Hydrogen from a hydrocarbon, ultimately leading to the formation of a carbonyl radical centre, ultiamtely two abstracted carbon radicals will bond to form a C2H6
- This effects the lipid membrane constructs of the mito, membrane, organelles, lysosomes etc.
How will aggregates encourage other proteins to misfold?
Through a process described as permissive templating, in which the misfolded protein acts as a template. Its highly exposed hydrophobic surface acts to attract protein structures of a folded proteins, encouraging segments to misfold.
Whats the correlation between increased protein concentration and protein aggregation?
It is a positive correlation, it has been sugggested as the increase in protein synthesis is often coupled with an increase in degradation processes
What do the Guiniers curve show
Using SAXS and SANS guinier curves were generated to show increased IgG concentration is coupled with increased aggregation.
What is the evidence of misfolding occuring during translation?
There has been evidence of the upregualtion of HSP in Htt models
What is the evidence of upregualtion of synthesis?
Triplifications in the SNCA gene
What is evidence for decreased proteasomal effects in PD?
o Substantia nigra in PD patients have decreased proteasomal activity
o Inhibition of UPS in mice can mimic some PD features
o Lewy bodies are ubiquitinated
o Homozygous mutations of the E3 ligase Parkin are rare but important autosomal recessive cause of PD
o UCL-H1 mutation seen in a family with PD
What is evidence for decreased proteasomal effects in AD?
o Striatum from HD patients has decreased proteasomal activity
o Htt aggregates are ubiquitinated
