Parkinson's disease

Question 1

what is parkinson’s disease?

Answer 1

A neurodegenerative movement disorder that affects doperminergic neurons of the substantia nigra

Question 2

what are the similarities between chronic neurogenerative disorders?

Answer 2

protein misfolding and aggregation
progressive symptoms that reflect the area affected, manifestation in the elderly

Question 3

Parkinson’s is a movement disorder characterised by what clinical symptoms?

Answer 3

difficulty in initiating voluntary movement
shuffling gait
resting tremor
rigidity

Question 4

when was/ who discovered Parkinson’s disease?

Answer 4

Parkinson’s disease was first medically described as a neurological syndrome by James Parkinson in 1817,

Question 5

what is the pathological hallmark of Parkinsons disease?

Answer 5

loss of dopaminergic neurons in substantia nigra
presence of lewy bodies

less modification -> less control of movement

Question 6

how can we see the pathological hallmark of parkinsons from slices of midbrain?

Answer 6

neurons of the substantia nigra are highly pigmented
when we cut secition of the midbrain where a portion of the substanita nigra is visible we see diminished pigmentation ie greatly reduced numbers of neurons in the substantia nigra

Question 7

what percentage of neurons can die before clinical symptoms of parkinsons start to manifest?

why does this occur?

Answer 7

80%
because existing neurons try to compensate for those that have been lost – could have had it for 20 years

Question 8

describe the direct pathway?

Answer 8

Excitatory info comes from cortex to the striatum
From there, inhibitory neurons project directly to the globus pallidus internus
Globus pallidus internus sends inhibitory neurons to the Thalamus
So less inhibition is sent to the Thalamus, therefore the Thalamus can send more excitatory info to the cortex
Substantia nigra sends excitatory dopamine to the striatum, taken by d1 receptors which enhances the excitation loop (the nigrostriatal dopamine pathway that is thought to be crucial in the facilitation of movement)

Question 9

describe an experiment that confirmed the loss of substantia nigra neurons are those responsible for parkinsosn symptoms

Answer 9

Stuck electrodes into animals and passed a current through to kill the cells – onto both sides or onto one side for complete or incomplete lesion. (sham is control, electrode but no signal)
Looked at tyrosine hydroxylase (an enzyme present in dopaminergic cells) they counted the cells that were positive for tyrosine hydroxylase and found that there was a dose dependent reduction in TH cells showing you that you could successfully lesion the substantia nigra
Then test whether this is what gives the locomotor phenotype
Animal put on revolving rod and it grips on and doesn’t fall of (if locomotor activity is strong) – if locomotor activity is not very strong then they cant hold on – sham animals didn’t fall of but lesion ones did
Did other field tests but all showed that just as there dose dependent reduction in the substantia nigra cells there was a dose dependent reduction in their locomotor capabilities – demonstrating causality

Question 10

what are lewy bodies composed of?

Answer 10

A halo around a darkened central core composed of alpha synuclein with ubiquitin on the surface

Question 11

what are the causes of sporadic parkinsons disease?

Answer 11

unknown cause
drug abuse - MPTP (early onset)
chemical exposure - pesticides
personality type

Question 12

what are the possible familial/genetic causes of parkinsons disease?
(4)

Answer 12

DJ-1 autsomal recessive
PINK-1 autosomal recessive
Parkin autsomal rec – juvenile onset
Synuclein mutations – juvenile onset

Question 13

what percentage of parkinsons has a familial cause?

Answer 13

10-15%

Question 14

how was the relationship between MPTP and parkinsons discovered?

Answer 14

In a large american city 40 years, lots of yound people, who were drug addicts, came to the ER with symptoms that looked like parkinsons
It turns out they drug abusers were trying to formulate a homemade version of a type of drug and inadvertantly created MPTP which had the ability to kill substantia nigra neurons

Question 15

how was MPTP confirmed to be a cause of parkinsons?

Answer 15

Injection of MPTP into monkeys, found a dramatic reduction in substantia nigra dopaminergic neurons.
Also looked at the behaviour – normal monkey is active when lights on and asleep when lights off. In monkeys with MPTP injection, they had very little activity at all times
At certain intervals tehy were given dopamine injections. Before they got the dopamine injected, all of the activity in the daytime hours are low, but when injected with dopamine they had increased activity, when this died down they had very little activity again

Question 16

during production of what drug can MPTP be accidnetally produced?

Answer 16

While MPTP itself has no psychoactive effects, the compound may be accidentally produced during the manufacture of Desmethylprodine (MPPP), a synthetic opioid drug with effects similar to those of morphine and pethidine (meperidine)

Question 17

what occured that highlighted the connection between pesticides and parkinsons?

Answer 17

Those living in communities where pesticiedes are sprayed in nearby crops had a much higher prevalence of parkinsons that the date from epidemiological studies suggested
this was particularly high in the farmers

Question 18

what compound in pesticides was a nigratoxin

Answer 18

Rotenone

Question 19

describe the study that confirmed the compount in pesticides caused parkinsons?

Answer 19

Treated drosophilia with Rotenone
reduction in dopaminergic neurons was seen after rotenone treatment
as well as a decreased ability to climb to the top of the chamber

Question 20

what personality type may have a causal link to parkinsons?

Answer 20

reclusive

Question 21

ultimately what is the difference between familial and sporadic froms of parkinsons?

Answer 21

pathology is the same but familial forms tend to affect people much younger

Question 22

why would pharmaceutical companies ‘recycle’ drugs?

Answer 22

to avoid having to go through all of the toxicity testing - a faster clinical development and testing timeline, and cheaper

Question 23

what clues do we have to the pathogenic mechanism of parkinsons disease?

Answer 23

MPTP inhibits mitochondrial complex 1
DJ-1 protects against Free Radical production
PINK1 localised to mitochondria
- all suggesting mitochondrial involvement - Free Radical production leads to oxidative stress

Parkin is an E3 ubiquitin-prn ligase
a-syn is a substrate for parkin
- reduced capacity of UPS to clear prns

mutant a-syn readily forms filaments
filaments  space occupying lesions
impaired chaperone activity?

a-syn interferes with trafficking

prion like transmission of misfolded alpha-syn oligomer

Question 24

give three reason why parkinsons is thought to arise due to mitochondrial dysfucntion

Answer 24

MPTP inhibits mitochondrial complex 1
DJ-1 protects against Free Radical production (if mutated with autosomal recessive inhertiance then no protection from FR)
PINK1 localised to mitochondria (suggesting it enable normal mitchondrial function, if mutated can no longer perform this function)

both sporadic and familial causes are involved in mitochondrial function

Question 25

why are the substantia nigra neurons particularly vulnerable to parkinsons?

Answer 25

it is not known but thought to be related to the enhanced mitochondrial function and higher energetic demand of dopaminergic neurons
this could mean that free radical accumulate much quicker making it harder for the cells to remove them before damage occurs

also antioxidant capacity might be lower

Question 26

what reason is there to doubt that parkinsons has a prion like spread?

Answer 26

because even though the injected lysate spreads throughout the brain over time, pathology doesnt spread with it and only neurons of the substantia nigra are affected

Question 27

give five pathological/moleculer causes of parkinsons

Answer 27

1. perturbed mitochondrial function causing free radical production leading to oxidative stress
2. reduced capacity of UPS resulting in inadequate clearance of misfolded prns and accumulation of misfolded prns
3. increased aggregation of alpha synuclein which form into filaments resulting in space occupying lesions
4. disruption of vesicular transport
5. prion like spreaf of alpha-syn oligomers

Question 28

what therapies are available to those with parkinsons?

Answer 28

Enhance dopaminergic transmission/
deep brain stimulation
disease modifying strategies

Question 29

what could arrest neurodegeneration in parkinsons disease?

Answer 29

anti-aggregation agents
neuroprotective agents antioxidants, a/inflam, neurotrophic factors
clear lewy bodies PD vaccine (anti- asyn)
agents to promote vesicular trafficking
cell transplantation
prevent transmission of oligomers

Question 30

give four things that need to be considered in creating Parkinsons therapies

Answer 30

wearing off (dopaminergic enhancers)
hypersensitivity
infections (pacemaker)
arresting neurodegeneration or postponing it?

Question 31

what consideration do we need to make for cell transplantation treatment, particularly putting stem cells in the substantia nigra

Answer 31

We don’t have the means to tell the cells to stopping differentiating – could lead to cancer
Ethical considerations
Elderly people have to go through traumatic sugery and the cells have to grow which they may not have time for
What kills the first substantia nigra might still be there to kill the new substantia nigra cells

Question 32

how can deep brain stimulation be used to treat parkinsons?

Answer 32

Electrode attach deep into brain into substantia nigra to increase electrical activity and excitation of the circuit

Question 33

what could be the potential downfalls of deep brain stimulation for parkinsons disease?

Answer 33

Very invasive – cant offer anybody, need specialist hospitals and staff, has to be kept very clean
May affect other systems in the brain – mood system, too much dopamine could precipitate hallucinogenic effect or mood disorders
Youre doing nothing to stop the degeneration – only replacing the function of the dead ones
High risk of infection to a very important area

Question 34

give five examples of drugs that compensate for dopamine loss

Answer 34

1. L DOPA - increase DA production
2. Selegline - decrease DA breakdown
3. Amantidine - stimulation DA release and inhibit reuptake
4. Apomorphine - stimulation DA receptors
5. COMT inhibitors - decrease DA degredation

Question 35

describe how L-Dopa substitutes for the lack of dopamine in parkinsons

Answer 35

increases dopamine production because it provides more substrate (L-DOPA) to be converted into dopamine

Question 36

describe the pharmacological mechanism of selegiline

Answer 36

Reduce dopamine breakdown – Selegline will act on the monoamine oxidase enzymes (enzymes that break down dopamine) (MAO-B)

Question 37

describe the pharmacological mechanism of amantidine

Answer 37

stimulates dopamine release and inhibits its reuptake

(by weakly agonising NMDA receptors)

Question 38

describe the pharmacological mechanism of apomorphine

Answer 38

stimulates dopamine receptors
( a molecular mimic of dopamine )

Question 39

describe the pharmacological mechanism of COMT inhibitors

Answer 39

prevent dopamine degredation

(inhibit catechol o methyl transferase (COMT), The COMT enzyme degrades catecholamines, including dopamine. )

As a consequence of these peripheral effects, central deliv- ery of levodopa is enhanced and levels of dopamine in the brain are increased. This effect is seen even with entacapone, a COMT inhibitor that does not cross the blood-brain barrier.

Question 40

describe how to arrest neurodegeneration in pd

Question 41

give a reason why the brain is susceptible to proteins in neurodegenerative disease?

Answer 41

Tissues composed primarily of postmitotic cells, such as the brain, which contains postmitotic neurons and oligodendrocytes, are especially sensitive to the effects of ageing, primarily because postmitotic cells are believed to be more vulnerable to DNA damage than proliferating cells

Question 42

what drug increases dopamine production for PD therapy?

Answer 42

L-DOPA

Question 43

what drug decrease dopamine breakdown by inhibiting monoamin oxidases?

Answer 43

Selegline

Question 44

What drug stimulates dopamine release and inhibits reuptake?

Answer 44

Amantadine

Question 45

give an example of a dopamine agonist for PD therapy

Answer 45

Apomorphine

Question 46

what drug inhibits dopamine degedation for PD therapy?

Answer 46

COMT inhibitors

Question 47

what effect do acetylcholine inhibitors have of parkinsons disease?

Answer 47

block Ach in the striatum

decrease in dopamine that allows acetylcholine to take over. When this occurs, muscles become too “excited,” which leads to symptoms such as jerking movements and tremors
ChIs are effective in the treatment of cognitive impairment in patients with PD, but do not affect risk of falls. The choice of treatment has to be balanced considering the increased tremor and adverse drug reactions

Question 48

How does Deep Brain Stimulation work?

how is it set up?

Answer 48

DBS is designed to use electrical currents to target abnormal brain activity – it triggers blood flow and a series of chemical reactions that leads to the release of neurotransmitters together to correct malfunctioning connections in the brain
Together neurologists and specialists take/fuse MRI and CT scans of the lesion to locate the area of the brain that will be targeted, doctors then surgically implant electrodes on the targeted area of the patients brain using a thin probe called a lead. Attached to the lead is a wire than runs through the head and neck under the skin to the chest where it attaches to a battery charged pulse generator that initiates electrical impulses. Doctors turn on the lead to begin sending electrical impulses to the brain, the patient may be asked to move an arm or something to ensure that the lead was implanted precisely.
A few weeks after the surgery the patient visits the neurology specialist who programs the strength, length (how long it lasts) and timing (how many times per sec) of the pulses delivered. Once the DBA device is programed it delivers electrical stimulation day in day out, tweaks are made according to patient profiles and the condition it is used to treat.

Question 49

what are some of the proposed pathogenic mechanisms for parkinsons disease?

Answer 49

Oxidative stress, accumulation of a-syn filaments, compromised UPS and defective vesicular trafficking are all proposed pathogenic mechanisms.

Possibly that the mutated parkin or synuclein result in reduced capacity of UPS to clear prns, resultign in aggregation of alpha-syn which then form space occupying lesions (lewy bodies) that disrupts vesicular transport.
The mutated mitochondrial proteins result in increased oxidative stress which also could cause reduced capcity of UPS to clear prns

Question 50

describe an experiment that studied the potential for stem cell transplant in the treatment of parkinsons

Answer 50

Cell transplantation studies done 25 years ago in Sweden to treat parkinsons disease. Embryonic tissue used.
Take tissue from the ventral mesosenthalic area of the brain (important for areas affect by parkinsons, substantia nigra and alike).
Cells taken from the embryo dissociates, prepared and then transplanted into human patients to treat parkinsons disease alogn with immunosuppressive drug.
Pretty good results – ethically challenging. Not a cure but saw some improvement.

Question 51

what is the effect of dopaminergic neuron loss in the substantia nigra?

Answer 51

loss of Dopaminergic neurons in the substantia nigra means that there is less modification and less control over modulation of the circuit. because the signals to the globus pallidus is imbalanced

It is as if all of the motor programs stored in cortex are constantly inhibited by the indirect pathway, with not enough excitation of the direct pathway for the desired motor program to become activated.

normally substantia nigra dopaminergic activity excites the direct pathway and inhibits the indirect pathway from the cortex

Question 52

what is the overall effect of the direct pathway?

Answer 52

To excite the cortex in order to promote movement

Question 53

describe the indirect pathway

Answer 53

Excitatory info comes from cortex into the striatum
From there, the striatum sends inhibitory info to the globus pallidus externus
The globus pallidus externus sends info which has less inhibition down to the subthalamic nucleus
So the subthalamic nucleus sends more excitatory info to the globus pallidus internus
Therefore the globus pallidus internus sends more inhibition to the thalamus
So the thalamus can’t send as much excitatory info to the cortex

Question 54

what is the effect of the indirect pathway?

Answer 54

helps to prevent unwanted muscle contractions from competing with voluntary movements.

Question 55

Describe how movement is initiated

Answer 55

The motor cortices send activating signals to the direct pathway through the basal ganglia, which stops inhibitory outflow from parts of the globus pallidus internus and the substantia nigra pars reticulata. The net effect is to allow the activation of the ventrolateral nucleus of the thalamus which, in turn, sends activating signals to the motor cortices. These events amplify motor cortical activity that will eventually drive muscle contractions

Question 56

what does the direct pathway control?

Answer 56

filters cortical information to regulate movement /
facilitates the initiation and execution of voluntary movement.