Parkinson's disease

Question 1

LO

Answer 1

• Be familiar with the clinical symptoms of PD.
• Recognise the pathological hallmarks of PD.
• Appreciate some of the proposed mechanisms that underlie this disease.
• Be familiar with the current therapies for PD.

Question 2

What is Parkinsons disease?

Answer 2

A Movement disorder

Question 3

Who does PD affect?

Answer 3

3-5% of over 65 year olds

Question 4

How common is PD?

Answer 4

2ND Most common ND disease

Question 5

What are some characteristics of PD that are similar to other ND?

Answer 5

Misfolded proteins, templated seeding, brain atrophy, lack of clearance of misfolded proteins, neuroinflammation

HD, familial AD and PD= elderly

Question 6

What are the clinical symptoms of PD?

Answer 6

• difficulty in initiating voluntary movement
• shuffling gait
• resting tremor
• rigidity

Question 7

What are the pathological hallmarks of PD?

Answer 7

Loss of dopaminergic neurons

Lewy bodies present in degenerating neurons

Question 8

Tell me about the pathway of the loss of dopaminergic neurons in the basal ganglia?

Answer 8

Question 9

Alongside the substantia nigra, what else helps with the modulation of movement?

Answer 9

The striatum of the basal ganglia i.e, caudate nucleus and putamen

Question 10

What some experimental evidence that dopaminergic neurons play a loss of motor control in PD?

Answer 10

Question 11

What are Lewy bodies composed of?

Answer 11

Alpha synuclein ubiquitin

The fact they contain UQ tell the body to remove it

Question 12

What are some of the causes of PD?

Answer 12

• Sporadic
• Genetic
• Lifestyle

Question 13

Tell me about some of the sporadic casues of PD?

Answer 13

• Unknown cause
• Drug abuse (MPTP (early onset))
• Chemical exposure i.e., pesticides
• Personality type

Question 14

Tell me about MPTP and some experimental evidence

Answer 14

MPTP inhibits mitochondrial function

MPTP leads to degeneration of substantial nigra

Experiment: give animal MPTP treatment. Did in monkey and found severe nerve cell loss in NMPTP- treated animals. Animals showed little movement until they received dopamine injections. Shows reliance on dopamine for movement as they were not making their own

Brain scans and autopsies on those juveniles who died with EOPD to confirm

Question 15

Tell me about the chemical exposure with pesticides

Answer 15

Link found via epidemiological studies

Need about 80% of circuitry to die before clinical symptoms are seen

Question 16

The link between personality type and parkinsons?

Answer 16

dopamine + anxiety/ schizophrenia , treated with L-DOPA…

Question 17

What is thought to be some genetic causes of PD?

Answer 17

DJ-1- autosomal recessive

PINK-1- autosomal recessive

Autosomal recessive needs two copies of defective gene to get disease so effects males and females equally. Recessive= LOF mutations

Parkin- autosomal recessive- juvenile onset

Synuclein mutations- juvenile onset

There are more which have since been identified

Question 18

The link between lifestyle and PD?

Answer 18

Envrionment factors which expose you to toxins

Question 19

What are some clues towards the pathogenic mechanisms of PD?

Answer 19

MPTP inhibits mitochondrial complex 1, it is a toxin

DJ-1 projects against Free Radical production

PINK1 localised to mitochondria

Free Radical production –> oxidative stress

Parkin is an E3 ubiquitin-protein ligase a-syn is a substrate for parkin

Reduced capacity of UPS to clear proteins (a degradation pathway)

Question 20

What do the clues towards the pathogenic mechanisms of PD suggest?

Answer 20

Reduced UPS activity from PD cybrids

UPS activity declines as we age- this may pre-dispose some to an accumulation of alpha-syn and therefore PD

Autophagy enhanced via rapamycin and metphormin

Question 21

What does the mutant a-syn (alpha-synuclein) form?

Answer 21

Mutations in a-syn make it more likely to fold into fibrils; this can have many conseuqences

1. fibrils can attract other proteins into them
2. fill up space
3. cause spatial lesions
4. acquire toxin gain of functions
5. less amenable to refolding by chaperones and degradation by the UPS

Question 22

Alternatively, are the aggregates protective – could pre-fibrils be toxic.

You should also be able to understand what can go wrong in the brain to give rise to epilepsy

Following on from that, you should understand how anti-epileptic drugs work

and finally, you should have some idea about what properties of antiepileptic drugs to take into consideration when prescribing them to patients.

Question 23

Filament –> space occupying lesions impaired chaperone activity?

Tell me the role of the chaperones

Answer 23

Chaperones help with misfolding of proteins to help refold. If they can’t then they target for degradation via UPS

Question 24

What else can a-syn interfere with?

Answer 24

Trafficking

Question 25

Some aspects of PD are said to act in a prion like fashion, tell me about this

Answer 25

prion like transmission of misfolded alpha-syn oligomer prion-like spread of disease? (doesn’t happen in just locomotor one?) Variants of PD. One which effects locomotor and one which effects locomotor and cognitive.

Question 26

What is alpha-synuclein?

Answer 26

Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. Biological process: negative regulation of neur... Cellular component: postsynapse; cytoplasm; ... Molecular function: calcium ion binding; protein ...

Question 27

What is the onset of events from a perturbed mitochondrial function?

Answer 27

Question 28

Why are SN DA neurones receptive?

Answer 28

Dopaminergic receptors are more energetically demanding so are more vulnerable in SN, as they have a greater reliance on dopamine? Similar structure? What do SN have that other structures don’t i.e., melanin?

Question 29

Outline some PD therapies

Answer 29

* Enhance dopaminergic transmission * Deep brain stimulation * Disease modifying strategies

Question 30

What are some therapies to enhance dopaminergic transmission? What may be some drawbacks to these therapies?

Answer 30

**Drawbacks:** Side effects Cells will still die so just boosting their function whilt they remain

Question 31

Tell me about the therapy of deep brain stimulation and some pros and cons to this therapy?

Answer 31

Stimulate SN via artificial circuit when tremors occur Good= pseudo circuit so doesn’t matter as much if all cells die Bad= specialist surgeons as serious consequences, expensive, will it have other detrimental effects? This is a transient relief for rigidity, tremor, doesn’t provide recovery of circuit loss just helps alleviate symptoms

Question 32

Tell me some disease modifying strategies for arresting the neurodegeneration in PD

Answer 32

Anti-aggregation agents Neuroprotective agents: antioxidants, a/inflame, neurotrophic factors Clear lewy bodies: PD vaccine (anti- alpha-syn) Agents to promote vesicular trafficking Cell transplantation --\> successful in animals with stem cells (how do you stop stem cells forming a tumour) Prevent transmission of oligomers

Question 33

Are these strategies for PD good enough?

Answer 33

Are these strategies good enough? What would their long-term side effects be? Wearing off (dopaminergic enhancers) Hypersensitivity Infections (pacemaker) Arresting neurodegeneration or postponing it?

Question 34

**Summary**

Answer 34

* **Know that PD is characterised by locomotor impairments** * **Know that lewy bodies and loss of dopaminergic neurones in the substantia nigra are the pathological hallmarks** * **Be familiar with the postulated sporadic and known familial causes of PD.** * **Appreciate that oxidative stress, accumulation of a-syn filaments, compromised UPS and defective vesicular trafficking are all proposed pathogenic mechansims.** * **Understand the current therapeutic interventions**

Question 35

Give an examle of an experimental mode of parkinsonism of laboratory animals and what paper was it discussed in?

Answer 35

Triarhou (2000-2013) * The injection of 6-hydroxydopamine (6-OHDA) into midbrain of rats an mice * causes acute degeneration of dopaminergic neurons * 6-OHDA recognised by nigral neurons as dopamine and is taken up into cell * enters the cytoplasm * 6-OHDA expresses toxicity and destroys monoaminergic cells selectively

Question 36

Give an experimental example that showed MPTP toxic effect, what paper was it in?

Answer 36

Triarhou (2000-2013) * MPTP is a toxin that causes PD in humans * MPTP molecule is selectively neurotoxic for human and nonhuman primates * used to induce PD in monkeys * in vitro, has shown that once in the cell MPTP becomes oxidised to MPP though the action of monoaminooxidade B * MPP is the form that is toxic to dopaminergic neurons