Lecture neurodegenerative disorders 4: synucleopathies (Parkinson's)

Question 1

Name four characteristics of Parkinson’s disease.

Answer 1

Parkinson’s is a movement disorder, symptoms are:

• bradykinesia (slow movement)
• rigidity (stiff movement)
• Resting tremor (shaking movement)
• Postural instability

Another symptom can be hypomimia (decreased facial expressions)

Question 2

What primary brain area is affected?

Answer 2

The substantia nigra, there’s loss of melanin containing dopaminergic neurons.

Question 3

What pathway is affected in Parkinson’s Disease and what’s the importance of this pathway?

Answer 3

The nigrostriatal pathway is affected, this pathway consists of neurons reaching from the substantia nigra to the caudate nucleus and putamen. It’s important in movement control.

Question 4

Shortly describe how the motor cortex regulates muscle activity in healthy state.

Answer 4

In healthy people, the motor cortex initiates two signals:

• one signal passes from the motor cortex to the reticular formation and spinal cord, which stimulates conctraction of muscles
• the other signal passes from the motor cortex to the basal ganglia. Here, dopamine dampens the effect of the motor signal. If dampening of the signal becomes too strong, acetylcholine can counteract the effect of dopamine, thus maintaining a balance in the force of the signals sent to the muscle.

Question 5

Descibe how Parkinson’s results in increased muscle tension and tremor.

Answer 5

In PD, degeneration of the basal ganglia and with this dopaminergic neurons of the substantia nigra results in a decrease of available dopamine. While the motor cortex is still able to pass a signal to the reticular formation and spinal cord, this signal is no longer dampened by dopamine. In combination with acetylcholine still able to ‘inhibit the dampening effect of dopamine’, there’s uncontrolled muscle movement like increased muscle tension and tremor.

Question 6

This pictures supports the previous questions. Just study.

Answer 6

Ok

Question 7

How is PD diagnosed?

Answer 7

Diagnosis with DAT-SPECT (dopamine transporter-SPECT). Here, a radioactive tracer is injected into the blood , where it circulates around the body and makes its way into the brain. It binds to dopamine transporters found on dopamine neurons. This can be visualized with a SPECT-scan.

Question 8

Like Alzheimer’s, there are also Braak stages for Parkinson’s. Describe these stages.

Answer 8

• Braak stages 1 and 2 → autonomic and olfactory disturbances
• Braak stages 3 and 4 → sleep and (pre)motor disturbances
• Braak stages 5 and 6 → emotional and cognitive disturbances

Question 9

What aggregate initiates development of Braag stages and how does it spread?

Answer 9

Lewy body aggregates. These aggregates first arise in the brainstem and spread via the olfactory bulb to the prefrontal cortex.

Question 10

What’s the first symptom that’s important for early diagnosis?

Answer 10

Loss of smell or reduced ability to smell due to the fact that the olfactory bulb is affected, which is responsible for the sensation of smell.

Question 11

Based on this picture, what can be stated/concluded?

Answer 11

That there’s extensive pathology before diagnosis, where the first part of development of the disease is a presymptomatic phase and the last part is a symptomatic phase. Also seen in this picture.

Question 12

What aggregates/neuronal inclusions belong to the pathology of Parkinson’s?

Answer 12

a-synuclein aggregates, also called Lewy bodies.

Question 13

What is a-synuclein?

Answer 13

A small synaptic protein that is involved in (pre)synaptic vescile fusion.

Question 14

Lewy bodies aggregate inside neuronal cell bodies (Lewy neurites). What kind of processes are disrupted/what does formation of Lewy bodies inside the cell cause?

Answer 14

• Oxidative stress
• Disruption of axonal transport
• Protein sequestration
• Mitochondrial dysfunction
• Synaptic dysfunction
• Inhibition of ubiquitin/proteasome system

Question 15

Answer the following questions:

1. How common is early-onset PD?
2. If someone has early-onset PD, how high is the probability for a monogenic cause?
3. Name risk genes for familial PD
4. Name risk genes for sporadic PD

Answer 15

1. Not common, only 15% is early-onset and 85% is late-onset PD.
2. The probability for a monogenic cause is very high when it is early-onset PD.
3. Risk genes are Parkin, Pink1, DJ1, LRRK2, SNCA
4. Risk genes are LRRK2, Parkin, PINK1, DJ1 (rare, but very limited data)

Question 16

In this picture the structure of a-synuclein is depicted. Explain what can happen in these regions.

Answer 16

• Amphipathic region (N-terminal domain) is composed of KTKEGV repeats where human missense mutations associated to familial PD have been found.
• The NAC domain/central hydrophobic core promotes aggregation of the protein
• The acidic tail/C-terminal domain contains phosphorylation sites and calcium binding site.

Question 17

Are lewy bodies ubiquitin positive?

Answer 17

Yes, only the question is left whether this is a cause or consequence.

Question 18

Answer the following questions:

• What causes alpha synuclein aggregation?
• What happens after alpha synuclein aggregates?

Answer 18

• SNCA mutations or multiplications
• This causes cytoplasmic accumulation of alpha synuclein, formation of toxic oligomers and formation of lewy bodies. This leads to mitochondrial dysfunction and ultimately neuronal death (gain of toxic function). And of course, due to the mutation/duplication, alpha synuclein function is altered and vesicle transport is impaired (loss of normal function).

Question 19

Answer the following questions:

• What causes dysfunction of the ubiquitin proteasome system (UPS)?
• What happens if UPS is affected?

Answer 19

• Mutations in UCHL1, PARK2 or DJ1 gene.
• UPS dysfunction causes cytoplasmic accumulation of alpha synuclein and lewy body formation.

Question 20

Answer the following questions:

• What causes mitochondrial dysfunction?
• What happens if there’s mitochondrial dysfunction?

Answer 20

• Mutations in PARK2, PINK1 or DJ1.
• It causes neuronal death

Question 21

What can be concluded based on dysfunction of the Ubiquitin Proteasome System (UPS), mitochondria and ROS?

Answer 21

That these play a central theme in Parkinson’s. Impairment of these processes are all implicated in alpha synuclein aggregation.

Question 22

What’s the difference between Parkinson’s disease and Parkinsonism?

Answer 22

Parkinsonism has symptoms that resemble Parkinson’s disease, but the aetiology is different.

This means that patients with Parkinsonism, on the outside appear to have PD. Only in the brain, no lewy bodies are present, but there is neuronal loss in the substantia nigra.

Question 23

Describe how we can study Parkinsonism in mouse models.

Answer 23

Here, MPTP (contaminant in heroin) is injected in mice, which induces Parkinsonism. In the brain, MPTP is taken up by glial cells and converted to MPP+. MPP+ is taken up and kills complex I of mitochondria, which leads to mitochondrial dysfunction and neuronal loss.

Note that this really can only be used to study Parkinsonism and not Parkinson’s disease. This is because, no alpha synuclein aggregations are used for this model.

Question 24

What do models for Parkinson’s disease and models for Parkinsonism have in common? And what difference is there?

Answer 24

• In common: dopaminergic neuronal loss
• Difference: aggregates, present in PD but not in Parkinsonism.

Question 25

Microglia are activated upon neurodegeneration in Parkinson's disease. How?

Answer 25

In Parkinson's disease, there's neuronal death caused by alpha-synuclein aggregates. Death of neurones causes release of neuromelanin, which triggers neuroinflammation. Here, microglia cells are activated, which leads to the release of all sorts of toxic cytokines. This leads to more degeneration of dopaminergic neurons (**positive feedback**).

Question 26

Is Parkinson's disease defined by dementia?

Answer 26

No, not entirely. It's primarily a movement disorder, but it can cause dementia (PDD). Dementia is caused by the spreading of neuronal loss to the cortical brain areas. This happens to 50% of patients.

Question 27

What's dementia with Lewy Bodies (DLB)?

Answer 27

DLB develops in 10-15% of dementia patients, with age of onset 75 years. It is a sporadic disease with alpha synuclein inclusions (i.e. lewy bodies) in the brain, which also causes dopaminergic neuronal loss. Only, these aggregates are not located in the substantia nigra, but in cortical brain areas. This is also the reason why dementia is much more prevalent than Parkinson's in DLB.

Question 28

What is the clinical diagnosis of Dementia with Lewy Bodies?

Answer 28

Patients should have at least 2 of the 3 symptoms: * Fluctuating cognition and attention * Visual hallucinations * Parkinsonism

Question 29

# Fill in whether AD- or DLB patients have more/less of the same symptoms compared to each other. * Memory impairment is \*more/less\* prevalent in AD-patients. * Hallucinations are \*more/less\* prevalent in DLB-patients.

Answer 29

* Memory impairment is **more** prevalent in AD-patients. * Hallucinations are **more** prevalent in DLB-patients.

Question 30

Parkinson's disease (PD) and Parkinson's disease dementia (PDD) both have alpha synucleinpathies and Lewy bodies. It's thought that these two disease lie on the same spectrum. This is not the case for dementia with lewy bodies (DLB), patients with DLB even get misdiagnosed quite often. What's so dangerous about this?

Answer 30

These patients are then treated with Haldol. Haldol is a dopamine antagonist, which makes DLB even worse. This is because in DLB patients, dopaminergic pathways are also affected. So DLB treatment is more like PD treatment, where medicine that promote dopaminergic signalling are used instead of medicine that block dopaminergic signalling.

Question 31

What is deep brain stimulation?

Answer 31

Stimulation of different brain areas with electrodes.

Question 32

What brain areas are stimulated for therapy of the following: * Global treatment of PD * Tremor * Rigidity and hypokinesia

Answer 32

* Global treatment of PD → nucleus subthalamicus * Tremor → thalamus * Rigidity and hypokinesia → globus pallidus

Question 33

Deep brain stimulation is a symptomatic treatment. What other promising treatment is there that is able to do more than only treat PD symptomatically?

Answer 33

Stem cell transplantation. Here, either _blastocyst cells are isolated and used as stem cells_, _fibroblasts are induced for pluripotency_ (iPS) or _neural stem cells are isolated from fetal tissue_ (e.g. ventral mesencephalon). The dopaminergic neuronal precursors or the tissue that is rich in dopaminergic neuroblasts are then injected into a PD brain.

Question 34

Just study: in this picture you can see that neuronal stem cell transplantation of neurons rich in dopamine, are still present after 14 years and are still effective (long-term graft viability). Here, tissue is stained with dopaminergic markers.

Answer 34

Ok

Question 35

What's seen in this picture where long-term graft tissue is stained for microglia (CD45)?

Answer 35

An inflammatory response of microglia