Huntington and Parkinson's Disease

Question 1

Huntington’s Disease
(cause, onset and symptoms)

Answer 1

also known as chorea major
- genetic neurological disorder; autosomal dominant condition
- onset is around 40-50 yrs old
- most obvious symptoms: abnormal body movements called chorea and lack of coordination but also changes in mental abilities

Question 2

which symptoms present first in HD

Answer 2

personality changes seen up to 2 years before any motor symptoms

Question 3

Most common causes of death in HD patients

Answer 3

Pneumonia, heart failure, choking and nutritional deficiencies (sometimes suicide)

Question 4

Etiology

Answer 4

• Abnormal Htt gene is located on chromosome 4
• gene defect codes for abnormal huntingtin (htt)
• abnormal gene contains more than 36 CA repeats (def pathogenic once more than 39 repeats, but heterogeneity seen when 36-38 repeats)
• abnormal gene prob has new gain of function but unclear exactly what it does

Question 5

Flow chart from mutant gene to cell death

Answer 5

mutant huntingtin > interferes with transcription > aggregation of mutant protein formation of inclusions > cellular dysfunction > cell death

** is the aggregation itself detrimental or is it a cellular response to something bad

Question 6

Where does neuronal degeneration occur in HD?

Answer 6

frontal lobes, caudate nucleus (striatum) of the basal ganglia, temporal lobes (so loss of higher mental functioning, movements and sensations)

Question 7

HD is characterized by particular loss of..? What is it theorized that this loss leads to?

Answer 7

medium spiny GABAergic neurons in striatum which receieve DAergic output from midbrain
- loss of inhibition of the thalamus, so the thalamus increases its output to certain regions of the brain’s. cerebral cortex (may lead to disorganized, excessive (hyperkinetic). movement patterns of chorea

Question 8

How are HD symptoms managed

Answer 8

various meds to balance DA and GABA

Question 9

pharmacotherapy for:
motor chorea
cognitive
psychiatric

Answer 9

motor chorea: olanzepine, tetrabenazine (DA depleting agent), resperidone, sulpride, amantadine, benzodiazepines
(a lot of these are DA blockers which lead to depression)

cognitive: nothing. Maybe modafanil or cholinesterase inhibitors

psychiatric: SSRIs/SNRIs, TCAs for depression, neuroleptics and antipsychotics like olanzapine, sodium valproate as mood stabilizer

Question 10

dysfunction of DAergic system associated with

Answer 10

• PD
• ADHD
• drug abuse
• SZ and affective disorders

Question 11

Physiological role of DA

Answer 11

• motor control
• cognition
• emotion/affect
• reward mechanisms

Question 12

RLS of DA synthesis and a blocker of it

Answer 12

tyrosine hydroxylase
- AMPT inhibits TH

Question 13

Most cases of PD are described as ___

Answer 13

idiopathic (unknown etiology)
- evidence for both genetic and environmental components (genetic mutations account for only 5-10% of cases and some are dominant while others are recessive)
- maybe pesticides

Question 14

PD affects which NT systems?

Answer 14

catecholamine system - includes DA

Question 15

Neurodegeneration in PD?

Answer 15

loss of neurons in SN leading to DA depletion
- once DA is depleted 60-80% the resultant changes in motor circuitry thought to underlie manifestations of PD

Question 16

Lewy bodies mainly contain

Answer 16

alpha synuclein and ubiquitin

Question 17

PD diagnosis in humans

Answer 17

done post-mortem
- stain for DA transporter because only DAergic neurons have DA therefore no DAT = no DAergic neurons (cell loss)

Question 18

Symptoms of PD

Answer 18

• tremors
• freezing
• reduced gait (smaller length of step)

Question 19

Genes associated with PD (autosomal dominant and autosomal recessive)

Answer 19

Dominant:
SNCA - alpha synuclein
LRRK2 - leucine-rich repeat kinase

Recessive:
Parkin - Parkin
PINK1 - PTEN-induced putative kinase 1
DJ-1 - DJ-1

BUT BASICALLY REMEMBER that different genes at different loci with different inheritance patterns can cause PD

Question 20

MPTP

Answer 20

by-product of MPPP synthesis which is a synthetic opioid (analog of Demerol)
- causes severe parkinsonism in young adults due to contaminated supply of MPPP

Question 21

How is MPTP toxic?

Answer 21

MPTP converted by MAO-B to its toxic metabolite, MPP+
- it’s charged so cant enter neuron without a transporter
- MPP+ is a substrate of the DA transporter so can enter DAergic cells
- inhibits complex I of Electron Transport Chain (DA neurons particularly sensitive to oxidant damage)

Question 22

Deprenyl

Answer 22

MPTP antidote - inhibits MAO-B so prevents conversion of MPTP to MPP+
- prevents nitrosylation of. GAPDH which complexes with MPP
- without the nitrosylation, the MPP+ complex cant go into the cell and inhibit complex I

Question 23

GBR 12909

Answer 23

Prevents uptake of MPP+ into cells

Question 24

Why is MPTP not a perfect model of PD?

Answer 24

no Lewy bodies or inclusions seen and also does not lead to a progressive disease state - immediate onset

Question 25

Ways of measuring DA cells

Answer 25

can count each cell (direct) or can measure DA levels to infer cell count (indirect measure)

Question 26

Dopamine synthesis

Answer 26

Tyrosine -(TH)-> DOPA -(AADC)-> DA

Question 27

Knowing dopamine synthesis, suggest possible. therapies for PD?

Answer 27

PD is a loss of DAergic cells so maybe you can:
- increase RLS step of DA synthesis
- create DA receptor agonists
- reduce DA degradation

Question 28

Most prevalent and effective drug used for PD treatment

Answer 28

L-DOPA or Levodopa (intermediate)
- can’t just give DA it wont cross BBB
- pre-drug metabolized to DA by aromatic-L-amino-decarboxylase (AADC) which increases DAergic output

Question 29

Problems with L-DOPA

Answer 29

• After 1-3 years of disease progression, monotherapy with levodopa becomes inadequate
  (in moderate and advanced disease, patients with motor fluctuations on L-DOPA may benefit from addition of a DA agonist)
• doesn’t actually reverse cell loss, just treats symptoms

Question 30

Early and late adverse drugs reactions to L-DOPA

Answer 30

early: hypotension (especially w high dose), arrhythmias, nausea, GI bleeding, disturbed respiration (not always harmful), hair loss

late: psychiatric symptoms, confusion, extreme emotional states and excessive libido, vidid dreams, visual and possibly auditory hallucinations, dyskinesias (erractic movements)

Question 31

Carbidopa and benserazide

Answer 31

90-95% of L-dopa metabolized in periphery leading to adverse events, so peripheral dopa decarboxylase inhibitors (AADCI) are given to prevent peripheral conversion and divert more L-dopa to brain
- lower the dose of L-dopa needed

Question 32

Problems with using rodent models of PD

Answer 32

Rodents have a MUCH more resilient DA system than us (natural selection - if rodents don’t move they die)
- you can kill 90% of a rat’s DAergic neurons and it’ll still be able to move, meanwhile a 60% reduction in humans will cause motor impairments
- can’t kill 100% of a rats DAergic cells cause then it can’t even feed

Question 33

New genetic mouse models for PD

Answer 33

Dopamine deficient DAT-KO (DDD) mice
- Excess DA in the synapse and no way to transport it back into cell terminal = no recycling
- KOing DAT depletes vesicular DA by 90%
- KO rodents go insane like theyre on speed/cocaine

Question 34

What happens when you inject a DDD mouse with TH-inhibitor? WT?

Answer 34

DDD - in a dopamine deficient DAT-KO mouse, a TH inhibitor will cause DA to drop to 0 because there is no vesicular DA to release when TH isn’t functioning
Motor activity drops to zero
- can rescue with L-dopa administration

WT - DA levels drop, but not to zero because there is DA stored in vesicles

Question 35

DA receptor agonists don’t work as well as providing L-Dopa. Propose a reason why this might be?

Answer 35

Maybe there’s a pulsatile way DA acts which is why a DAR agonist wouldn’t do the trick as well.