L23 - Parkinsons Disease

Question 1

Huntingtons Disease is due to a single gene where else PD is due to a whole range of factors. Normally, DA neurons have a tonic inhibition over ACh neurons,

Answer 1

Huntingtons Disease is due to a single gene where else PD is due to a whole range of factors. Normally, DA neurons have a tonic inhibition over ACh neurons,

Question 2

PD motor symptoms

Answer 2

Bradykinesia
Rigid limbs
Decreased manual dexterity

Postural reflex impairment
Impassive face - no blinking
Tremor
Speech - monotonous, hypophonic (soft)

Question 3

List some non-motor PD symptoms - which is the first one a PD person exp?

Answer 3

Olfactory deficiencies and bowel problems

Fatigue
Anxiety
Cognitive deficiencies

Depression
Insomnia
Pain
Sex dsyfunction

Question 4

In PD what bodies are present at post-mortem?

Answer 4

Lewy bodies - abnormal aggregates of protein that develop inside nerve cells and cause toxicity

Question 5

In PD, there is a mutation in parkin - what is it and how does it affect the cell?

Answer 5

Ubiquitin ligase

Ubiquitin is a tag that initiates protein degradation. If parkin is affected, proteins can’t get degraded and the cell gets filled up and apoptosis occurs

Question 6

What role does DJ-1 and PINK-1 play in PD?

Answer 6

Involved in mitochondria - mutations in these 2 genes lead to an increased amount of ROS = death

Question 7

Since PD people lack DA, would amphetamine and cocaine help?

Answer 7

No - as it has many other effects as well

Question 8

How does a cholinergic antagonist help treat PD? Musc or nic?

Answer 8

In the microanatomy of the CNS, DA has a tonic inhibition on Cholinergic neurons. As there is decreased DA neurons in PD, hence also a decrease in the inhibition of Cholinergic neurons.

Musc

Question 9

L-Dopa have over 90% of it metabolised in the periphery after it is converted into DA - mainly by ___ and some by ___-

Answer 9

Mainly by gut and some in peripheral tissues

Question 10

List 2 DDC inhibitors

Answer 10

Carbidopa

Benserazide

Question 11

Why does treatment using Carbidopa.Benserazide and L-Dopa decline over time?

Answer 11

PD symptoms exhibited when you’ve lost 60-80% of DA neurons - treatment requires functional DA neurons. Treatment declines over time as you lose more and more DA neurons overtime

The more drugs you take - it accelerates PD in some people because you are using the DA neurons

Question 12

What is Levodopa? Half-life? Side effects?

Answer 12

L-Dopa

1-2 hours - rapid absorption on empty stomach as it competes with other neutral a.acids

SE - anorexia, nausea, tachycardia, orthostatic hypotension, pupil dilation

Question 13

List 2 DA agonists

Answer 13

Bromocriptine

Cabergoline

Question 14

What ergoline-based DA agonist can be used in adjunct to L-Dopa?

Answer 14

Pergolide

Question 15

Why is MAOB inhibitor preferred over MAOA inhibitor?

Answer 15

MAOA inhibitor may cause hypertension

*Early use may delay disease progression by reducing formation of free radicals

Question 16

What drug is currently used as antiviral in influenza that enhances DA release?

Answer 16

Amantadine

• Less efficacious than L-DOPA and more rapid tolerance
• Has anticholinergic activity

Question 17

T/F - Deep brain stimulation works for PD patients

Answer 17

T

Question 18

What receptor antagonists interact with D2 receptors in basal ganglia to make the D2 receptors more sensitive to DA?

Answer 18

Adenosine A2a

Question 19

By antagonising ____, L-Dopa will be able to be used at a higher dose?

Answer 19

mGluR5

Question 20

2 suggestions to treat PD 5-10 years from now? 10-20 years?

Answer 20

Deep brain stimulation (DBS) and optogentics

Genetics, cell replacement therapy (induced pluripotent stem cells) - take a skin cell from patient and reprogram it then use another mix of genes to turn it into DA neuron (these cells avoid transplant rejection but also may be susceptible to the same disease process)

Question 21

What is the number 1 mutation in PD?

Answer 21

Alpha-synuclein - thread-like fibrils of stuck-together copies of this protein are found in Lewy body deposits inside neurons in affected brain areas

• Mutating or overproducing a-synuclein can cause PD
• small not large fibrils are the real toxic drivers of the disease
• Oxidized DA enhances stability of a-synuclein oligomers (bad thing)

Question 22

T/F - Smoking and drinking have been linked to lower incidence of PD (no one knows why)

Answer 22

T

Question 23

What is an early non-motor sign of PD

Answer 23

Gut and nose being affected

Question 24

Number 1 risk factor for PD

Answer 24

Age - could weaken mitochondria and reduce neuron’s ability to dispose of harmful alpha-synuclein aggregates

Question 25

List, in order from highest likely cause to lowest likely cause of PD (3)

Answer 25

1) Alpha-synuclein
2) Mitochondria - damaged or mutated release ROS
3) Pesticides increase chance of PD