Huntington and Parkinson's Disease Flashcards
Huntington’s Disease
(cause, onset and symptoms)
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
which symptoms present first in HD
personality changes seen up to 2 years before any motor symptoms
Most common causes of death in HD patients
Pneumonia, heart failure, choking and nutritional deficiencies (sometimes suicide)
Etiology
- 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
Flow chart from mutant gene to cell death
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
Where does neuronal degeneration occur in HD?
frontal lobes, caudate nucleus (striatum) of the basal ganglia, temporal lobes (so loss of higher mental functioning, movements and sensations)
HD is characterized by particular loss of..? What is it theorized that this loss leads to?
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
How are HD symptoms managed
various meds to balance DA and GABA
pharmacotherapy for:
motor chorea
cognitive
psychiatric
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
dysfunction of DAergic system associated with
- PD
- ADHD
- drug abuse
- SZ and affective disorders
Physiological role of DA
- motor control
- cognition
- emotion/affect
- reward mechanisms
RLS of DA synthesis and a blocker of it
tyrosine hydroxylase
- AMPT inhibits TH
Most cases of PD are described as ___
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
PD affects which NT systems?
catecholamine system - includes DA
Neurodegeneration in PD?
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
Lewy bodies mainly contain
alpha synuclein and ubiquitin
PD diagnosis in humans
done post-mortem
- stain for DA transporter because only DAergic neurons have DA therefore no DAT = no DAergic neurons (cell loss)
Symptoms of PD
- tremors
- freezing
- reduced gait (smaller length of step)
Genes associated with PD (autosomal dominant and autosomal recessive)
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
MPTP
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
How is MPTP toxic?
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)
Deprenyl
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
GBR 12909
Prevents uptake of MPP+ into cells
Why is MPTP not a perfect model of PD?
no Lewy bodies or inclusions seen and also does not lead to a progressive disease state - immediate onset
Ways of measuring DA cells
can count each cell (direct) or can measure DA levels to infer cell count (indirect measure)
Dopamine synthesis
Tyrosine -(TH)-> DOPA -(AADC)-> DA
Knowing dopamine synthesis, suggest possible. therapies for PD?
PD is a loss of DAergic cells so maybe you can:
- increase RLS step of DA synthesis
- create DA receptor agonists
- reduce DA degradation
Most prevalent and effective drug used for PD treatment
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
Problems with L-DOPA
- 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
Early and late adverse drugs reactions to L-DOPA
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)
Carbidopa and benserazide
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
Problems with using rodent models of PD
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
New genetic mouse models for PD
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
What happens when you inject a DDD mouse with TH-inhibitor? WT?
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
DA receptor agonists don’t work as well as providing L-Dopa. Propose a reason why this might be?
Maybe there’s a pulsatile way DA acts which is why a DAR agonist wouldn’t do the trick as well.
