Parkinson's disease

Question 1

What are the symptoms of Parkinson’s disease?

Answer 1

1. Rigidity and trembling of head
2. Slight leaning forward of the trunk
3. shuffling gait with short steps
4. Rigidity and trembling of extremities

Question 2

What are the two types of Dementia that can occur with PD?

Answer 2

1. Dementia with Lewy bodies (PLB)
2. Parkinson’s disease dementia (PDD)
   Note that pathologically, they are both the same

Question 3

What are the two types of PD?

Answer 3

There is Sporadic (random) or familial (genetic).

Question 4

Which of the two types of PD is most prevalent?

Answer 4

The sporadic PD is most prevalent. It is thought that toxins, metals or drugs like MPTP (the synthetic heroine) can all induce PD.

Question 5

What factors cause familial PD?

Answer 5

Mutations to genes associated with PD.
These genes are:
Alpha-synuclein (SNCA),
Parkin (PRKN),
Leucine-rich repeat kinase (LRRK2), 
DJ-1, 
PINK1.

Question 6

What happens to the substantia nigra dopaminergic cells to induce Parkinson’s disease?

Answer 6

The dopaminergic cells in the substantia nigra are responsible for motor control and their death (process still unknown) causes the PD symptoms.

Question 7

What is the percentage of dopaminergic cells that is lost by the time that PD symptoms are experienced?

Answer 7

60-70%. There is also discolouration of the substantia nigra from black to normal beige.

Question 8

What functions is the substantia nigra responsible for?

Answer 8

It controls voluntary movement and also produces dopamine for the region. It is found in the midbrain, and is part of the larger basal ganglia.

Question 9

From which region of the substantia nigra are most dopaminergic neurons lost?

Answer 9

Most of the neurons are lost from the ventrolateral region. This region is where susbstantia nigra neurons project into the striatum infront of it. The striatum is responsible for planning of movement. This is the origin of PD symptoms.

Question 10

No cure is present for PD. What drugs are used to help alleviate the symptoms of PD?

Answer 10

1. L-dopamine doses: L-dopamine is converted into dopamine in the brain. By increasing its concentration, this helps to increase the functionality of the remaining few dopaminergic neurons.
2. MAO-B inhibitors: They stop monoamine oxidase, which destroys excess dopamine in the synapses. This also allows dopamine levels to increase.
3. Dopamine agonists: mimic the effects of dopamine
4. Anti-cholinergic drugs- these stop the muscular tremors and stiffness.

Question 11

How does inflammation cause PD?

Answer 11

Inflammation activates microglial cells (resident macrophages of the brain), so that they can also kill neurons. Inflammation also causes increased levels of cytokines, which also mediate cell death.

Question 12

Can lewy bodies be present in individuals without PD?

Answer 12

Yes, especially in those over 60.

Question 13

What is the protein alpha-synuclein?

Answer 13

Alpha-synuclein is a largely unfolded protein that is linked to learning, synaptic plasticity and development.
It is also associated with dopamine release from the neurons.

Question 14

What factors cause alpha-synuclein to aggregate in the dopaminergic neurons?

Answer 14

1. Genetic mutations to alpha synuclein.

2. iron, oxidants, nitration and exposuretoenvironmentaltoxins.

Question 15

What is the relationship between alpha synuclein and dopamine?

Answer 15

Alpha synuclein will not aggregate to form an amyloid inside the neuron if it has dopamine with it. So, dopamine is protective.

Question 16

What affect does aggregated alpha synuclein have on the mitochondria of these neurons?

Answer 16

Normally, the alpha synuclein in its monomeric state has no effect on the mitochondria.
It is only when the alpha synuclein is aggregated into its oligomeric form that it binds to and rips apart the mitochondria into fragments. This induces apoptosis of the neuron. This process is called mitochondrial fragmentation.

Question 17

What is alpha synuclein’s role in vesicle transport of dopamine?

Answer 17

It is needed for recycling and reuse of neuronal dopamine vesicles after it has been emptied out. If alpha synuclein levels are low, there is increased dopamine per vesicle. If alpha synuclein is mutated though, then the vesicles are not recycled anymore.

Question 18

How is alpha synuclein disposed of by the neuron when it is not needed anymore (to prevent it sitting there and aggregating).

Answer 18

It is tagged with ubiquitin and cleared by the ubiquitin-proteasome protein pathway.

Question 19

What happens when you inject the toxic form of dopamine, 6-hydroxydopamine into the substantia nigra of mice?

Answer 19

6-hydroxydopamine induces oxidative stress in the substantia nigra, leading to neuronal death and activation of inflammation.

Question 20

What happens when you inject MTPT into the substantia nigra of mice?

Answer 20

MTPT is a synthetic drug that induces PD like symptoms. It is also induces lewy body formation. MTPT causes the nitration and thus aggregation of alpha synuclein. Alpha synuclein knockout mice are resistant to MTPT.

Question 21

Can alpha-synuclein spread to other regions of the substantia nigra, or is it confined to its neuron?

Answer 21

Alpha synuclein can spread to other neurons in the substantia nigra. It does this by first being released from the neuron in a vesicle, and then being taken up by a neighbouring neuron via endocytosis. The presence of aggregated alpha synuclein activates the microglial cells and inflammation starts.

Question 22

How are aggregated alpha synuclein fibrils removed from the neuron?

Answer 22

Amyloid fibrils of aggregated alpha synuclein can only be degraded by phagophores. Generation of phagophores is bad for neurons because it increases oxidative stress and aging.