Parkinsons Disease

Question 1

Similarities of chronic neurodegenerative disease

Answer 1

Clear symptoms that is to do with the circuits impacted
Symptoms progress over time
Misfolded and aggregation of proteins
They aren’t diseases of young people but can have early onset versions

Question 2

Why is the older brain more vulnerable

Answer 2

Exposure to environmental stressors which accumulated over time
Surveillance machinery which look for misfolded proteins worn out

Question 3

What is PD and who does it affect

Answer 3

Movement disorder
Affects the elderly usually (3-5% of over 65s)
Second most common neurodegenerative disease after AD

Question 4

Clinical symptoms of PD

Answer 4

Movement disorder
Difficult in initiating voluntary movement
Shuffling gait
Resting tremor
Rigidity

Question 5

What gives rise to the symptoms of PD (biological)

Answer 5

Loss of dopaminergic neurones in substrantia nigra
Less modification = less control
Symptoms only seen when 80% of neurones dead

Question 6

Evidence that loss of substantia nigra neurones cause the symptoms

Answer 6

Lesion the substantia nigra
Electrodes into animal brain
Complete lesion - 40% TH cells
Incomplete lesion - 60% TH cells
Sham lesion - 100% TH cells

Rotarod, open field tests

Question 7

Remaining neurones in PD

Answer 7

Lewy bodies in degenerating neurones
Misfolded and aggregated alpha synuclein and ubiquitin

Question 8

What does having ubiquitin imply

Answer 8

Targeted for degredation
But removal mechanisms insufficient as not removed

Question 9

What are the sporadic causes of PD

Answer 9

unknown causes, drug abuse (MPTP), chemical exposure (pesticides), personality type

Question 10

What are the genetic causes of PD

Answer 10

DJ-1 autosomal recessive, PINK-1 autosomal recessive, Parkin autosomal rec (juvenile onset), synuclein mutations (juvenile onset)

Question 11

What experiment could test that MPTP could cause PD symptoms?

Answer 11

Inject MPTP into monkeys
Recreate drug context

Normal: normal cells, light active, dark rest
MPTP: reduction in substantia nigra dopermenergic cells, given dopamine increases activity

Question 12

How could pesticides and PD be tested?

Answer 12

People who worked with pesticides/ near pesticides had higher prevalence of PD - epistemological studies
Rotenburg - nigra toxin
Fed to fruit fly, decreased doperminergic neurones compared to control in dose dependent study
Locomotion affected, could not climb chamber

Question 13

How are personality types more likely to get Parkinson’s disease

Answer 13

Reclusive personality types
Epidemiological studies/ what’s common between those who have PD
Depression related? - setotrnergic and adrenergic systems?

Question 14

How could you test depression cause of PD

Answer 14

Imaging to see if people with depression to see if there is substantia nigra loss (post mortem if after death)
Give PD patients who were reclusive round of antidepressants to see if there is an improvement (recycling drug)

Question 15

Excessive free radicals and oxidative stress mechanism causing doperminergic neurones to die (mutations)

Answer 15

MPTP inhibits mitochondrial complex 1
DJ-1 protects against FR production
PINK localised to mitochondria
(THESE ARE GENETIC FACTORS)

Question 16

Why are only the mitochondria in the substantia nigra effected by FR there?

Answer 16

Unknown but ideas:
Mitochondrial usage and energy demands are very high so more free radicals potentially produced quicker and not cleaned up so accumulate compared to others where slowly accumulate and can clear up FR
Antioxidant capacities lower there

Could test this in animal models

Question 17

Reduced capacity of UPS to clear prns

Answer 17

Parkin is an E3 ubiquitin-prn locate
A-syn is a substrate for Parkin

Ubiquitin system dysfunctional in Parkin so accumulation - a-syn accumulation could be toxic (reduced UPS from PD cybrids)

Question 18

Occupying function space of PD

Answer 18

Mutant a-syn readily forms filaments
Blockage
A-syn interferes with trafficking

Question 19

Prion like spread of disease of PD

Answer 19

Prion like transmission of misfolded alpha-syn oligomer
Took lysate from patients and inject into rodent - spread in other regions and not just injection site
BUT in PD will only have pathology in substantial nigra so not actually doing it in PD patients

Question 20

Summary of pathogenic mechanisms of PD

Answer 20

Perturbed mitochondrial function, free radicals and oxidative stress

Reduced capacity of UPS, inadequate clearance of misfolded prns, accumulation of misfolded prns

Increased aggregation of a-syn, filaments, space occupying lesions

Disruptions of vesicular transport

Question 21

Why are SN DA neurones most receptive?

Answer 21

High energetic demands
Not as much protective antioxidant capacities to match high demand

Question 22

PD therapies replacing or increasing dopamine

Answer 22

Compensate for dopamine loss by given more dopamine externally
L DOPA, selegline (decrease DA breakdown), amantidine, apomorphine (stimulate DA receptors), COMT inhibitors (other circuits impacted eg schizophrenia and hallucinations)

Deep brain stimulation, electrode, neurostimulator so excitation of circuit (invasive)

Both don’t stop neurones from dying

Question 23

Disease modifying strategies of PD

Answer 23

Reduce aggregation (inhibitors? Antagonist action to regions that self aggregate?)
Neuro protective agents (antioxidants, anti inflammatory, neurotrophic factors)
Clear Lewy bodies (PD vaccine) (brain very immune privilege so inflammation there can cause other major issues eg meningitis)
Promote cesicular trafficking
Cell transplantation (stem cells into SN region and encouraged into nigra neurones but don’t have means to tell those cells to stop so could become cancerous, thing that killed in the first place may still be there and do it again)
Prevent transmission of oligomers