PD Animal Models Flashcards
What are the two main categories of animal models of PD?
Toxin based
Gene based
Which toxin based models exist?
6-OHDA
Paraquat
Rotenone
MPTP
Which gene based models exist?
Synuclein
Parkin
What is 6-OHDA induced toxicity specific for?
DA neurons
How does 6-OHDA attack DA neurons?
Accumulates in cytosol to generate ROS
AND
Inhibits complex I
Describe 6-OHDA induced toxicity in the SNpc
Moderate but specific DA neuron depletion
What are the pros oft he 6-OHDA model of PD?
Good at testing new drug
What are the cons of 6-OHDA model?
May differ form humans
No Lewy body formation
What is MPTP?
Neurotoxin
How is the MPTP model of PD similar to human?
Preferential degeneration of putamen DA nerve
Cell loss in SNpc > VTA
DA neuromelanin cells are more susceptible to damage
How is the MPTP model of PD different to humans?
Only damages DA
No lewy body formation
What are MPTP models used for?
Novel drug treatment
Outline MPTP metabolism
Crosses BBB
Converted to NPDP+ but MAO-B in non-DA cells
Then to MPP+
MPP+ released from glial cells to take up DA
But then also take up MPP+
Why is it bad that cells take up MPP+?
Inhibits complex I to cause damage
What is paraquat?
Herbicide
Why is paraquat toxic if it doesn’t cross the BBB?
Forms superoxide radical to cause SNpc DA degeneration
Also a/w alpha-synuclein inclusions
What are the pros of paraquat models of PD?
Useful to study alpha-synuclein role in PD
What are the cons of paraquat models of PD?
Not known if it is selective for DA
What is the difference between MPP+ and paraquat?
The second N-methyl-pyridinium group
MPP+ - phenyl group
Paraquat - paraquat group
What is rotenone?
Widely used insecticide and fish poison
What do rotenone treated rodents develop?
DA degeneration
Alpha-synuclein inclusions
Abnormal posture
Slowness of movement
What are the pros of rotenone models?
Good for studying relationships between aggregate formation and cell death
What are the cons of rotenone models?
Not selective to DA
Describe the “quaking mouse mutant”
Spontaneous deletion of parkin
Leads to myelin deficiency and enhanced DA metabolism
Have tremor and behavioural defects
Describe Parkin KO mice
Progressive motor anomlies
Sensorimotor integration
But increased DA release?
What is 6-OHDA
Synthetic neurotoxic compound which selectively attacks DA neurons
How does rotenone work?
Interferes with the electron transport chain via complex I inhibition
Why does rotenone make a good model of PD?
Complex I is inhibited in PD b peroxynitrite
How does paraquat work?
Accepts electrons and transfers them to molecular oxygen to create ROS
