Parkinsons Disease

Question 1

How does neuronal death in Parkinsons disease lead to loss of movement control?

Answer 1

Parkinsons becomes symptomatic when a patient loses 60-80% of the substantia nigra. When lost, the direct pathway looses its stimulation (normally through activation of D1 receptors by the SN) and the indirect pathway looses its inhibition (normally through activation of D2 receptors by the SN).

Question 2

What potential therapies for Parkinsons disease are used?

Answer 2

As PD causes a lack of dopamine in the basal ganglia, therapy involves:

L-Dopa to replace cell L-Dopa levels
Selegeline - A selective irreversible monoamine oxidase inhibitor (which would normally metabolise dopamine)
Tolcapone - a catachol-O-methyl transferase inhibitor (which would normally (which would normally metabolise dopamine)
Pergoline - a dopamine receptor agonist.

Question 3

What are the causes of Parkinson’s disease?

Answer 3

Environment:
Neurotoxin MPTP was shown to induce parkinsonian syndrome however it is not in high enough concentration in the environment to cause it in humans. However its structure has been shown to be similar to some pesticicdes, and studies indicate a slight risk increase of PD to those exposed to pesticides, rural residence, farming and drinking well water.

Genetics:
5-10% of PD are genetic, genes shown to be involved include alpha synuclein and parkin

Question 4

What is the genetic bases of parkinsons disease?

Answer 4

Alpha synuclein:
Autosomal dominant gene whose product helps generate synaptic vesicles and aid their docking to membranes. When this is absent or not working, it prevents the release of dopamine, causing an increasing dopamine degradation. This produces reactive quinones which inhibit the mitochondrial electron transport chain, increasing oxidate stress. A-Syn mutants can also accumulate within he inner mitochondrial membrane, further disrupting the chain.

Parkin
Autosomal recessive gene which codes for E3 ubiquitin ligase, which ligates ubiquitin to alpha-synuclein. If there is a mutation is could lead to a dysfunctional a-syn (as old overused proteins become damaged) causing an increased intracellular dopamine resulting in oxidative stress as described above.