Lecture neurodegenerative disorders 4: synucleopathies (Parkinson's) Flashcards
Name four characteristics of Parkinson’s disease.
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)
What primary brain area is affected?
The substantia nigra, there’s loss of melanin containing dopaminergic neurons.
What pathway is affected in Parkinson’s Disease and what’s the importance of this pathway?
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.
Shortly describe how the motor cortex regulates muscle activity in healthy state.
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.
Descibe how Parkinson’s results in increased muscle tension and tremor.
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.
This pictures supports the previous questions. Just study.
Ok
How is PD diagnosed?
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.
Like Alzheimer’s, there are also Braak stages for Parkinson’s. Describe these stages.
- 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
What aggregate initiates development of Braag stages and how does it spread?
Lewy body aggregates. These aggregates first arise in the brainstem and spread via the olfactory bulb to the prefrontal cortex.
What’s the first symptom that’s important for early diagnosis?
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.
Based on this picture, what can be stated/concluded?
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.
What aggregates/neuronal inclusions belong to the pathology of Parkinson’s?
a-synuclein aggregates, also called Lewy bodies.
What is a-synuclein?
A small synaptic protein that is involved in (pre)synaptic vescile fusion.
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?
- Oxidative stress
- Disruption of axonal transport
- Protein sequestration
- Mitochondrial dysfunction
- Synaptic dysfunction
- Inhibition of ubiquitin/proteasome system
Answer the following questions:
- How common is early-onset PD?
- If someone has early-onset PD, how high is the probability for a monogenic cause?
- Name risk genes for familial PD
- Name risk genes for sporadic PD
- Not common, only 15% is early-onset and 85% is late-onset PD.
- The probability for a monogenic cause is very high when it is early-onset PD.
- Risk genes are Parkin, Pink1, DJ1, LRRK2, SNCA
- Risk genes are LRRK2, Parkin, PINK1, DJ1 (rare, but very limited data)
In this picture the structure of a-synuclein is depicted. Explain what can happen in these regions.
- 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.
Are lewy bodies ubiquitin positive?
Yes, only the question is left whether this is a cause or consequence.
Answer the following questions:
- What causes alpha synuclein aggregation?
- What happens after alpha synuclein aggregates?
- 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).
Answer the following questions:
- What causes dysfunction of the ubiquitin proteasome system (UPS)?
- What happens if UPS is affected?
- Mutations in UCHL1, PARK2 or DJ1 gene.
- UPS dysfunction causes cytoplasmic accumulation of alpha synuclein and lewy body formation.
What can be concluded based on dysfunction of the Ubiquitin Proteasome System (UPS), mitochondria and ROS?
That these play a central theme in Parkinson’s. Impairment of these processes are all implicated in alpha synuclein aggregation.
Describe how we can study Parkinsonism in mouse models.
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.
What do models for Parkinson’s disease and models for Parkinsonism have in common? And what difference is there?
- In common: dopaminergic neuronal loss
- Difference: aggregates, present in PD but not in Parkinsonism.
Microglia are activated upon neurodegeneration in Parkinson’s disease. How?
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).
Is Parkinson’s disease defined by dementia?
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.
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.
- Memory impairment is more prevalent in AD-patients.
- Hallucinations are more prevalent in DLB-patients.
Deep brain stimulation is a symptomatic treatment. What other promising treatment is there that is able to do more than only treat PD symptomatically?
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.
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.
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