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biol3048 > Parkinson's disease > Flashcards

Parkinson's disease Flashcards

1
Q

LO

A
  • 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.
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2
Q

What is Parkinsons disease?

A

A Movement disorder

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3
Q

Who does PD affect?

A

3-5% of over 65 year olds

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4
Q

How common is PD?

A

2ND Most common ND disease

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5
Q

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

A

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

HD, familial AD and PD= elderly

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6
Q

What are the clinical symptoms of PD?

A
  • difficulty in initiating voluntary movement
  • shuffling gait
  • resting tremor
  • rigidity
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7
Q

What are the pathological hallmarks of PD?

A

Loss of dopaminergic neurons

Lewy bodies present in degenerating neurons

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8
Q

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

A
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9
Q

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

A

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

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10
Q

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

A
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11
Q

What are Lewy bodies composed of?

A

Alpha synuclein ubiquitin

The fact they contain UQ tell the body to remove it

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12
Q

What are some of the causes of PD?

A
  • Sporadic
  • Genetic
  • Lifestyle
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13
Q

Tell me about some of the sporadic casues of PD?

A
  • Unknown cause
  • Drug abuse (MPTP (early onset))
  • Chemical exposure i.e., pesticides
  • Personality type
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14
Q

Tell me about MPTP and some experimental evidence

A

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

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15
Q

Tell me about the chemical exposure with pesticides

A

Link found via epidemiological studies

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

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16
Q

The link between personality type and parkinsons?

A

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

17
Q

What is thought to be some genetic causes of PD?

A

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

18
Q

The link between lifestyle and PD?

A

Envrionment factors which expose you to toxins

19
Q

What are some clues towards the pathogenic mechanisms of PD?

A

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)

20
Q

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

A

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

21
Q

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

A

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
22
Q

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.

A
23
Q

Filament –> space occupying lesions impaired chaperone activity?

Tell me the role of the chaperones

A

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

24
Q

What else can a-syn interfere with?

A

Trafficking

25
Q

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

A

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.

26
Q

What is alpha-synuclein?

A

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 …

27
Q

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

A
28
Q

Why are SN DA neurones receptive?

A

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?

29
Q

Outline some PD therapies

A
  • Enhance dopaminergic transmission
  • Deep brain stimulation
  • Disease modifying strategies
30
Q

What are some therapies to enhance dopaminergic transmission?

What may be some drawbacks to these therapies?

A

Drawbacks:

Side effects

Cells will still die so just boosting their function whilt they remain

31
Q

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

A

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

32
Q

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

A

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

33
Q

Are these strategies for PD good enough?

A

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?

34
Q

Summary

A
  • 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
35
Q

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

A

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
36
Q

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

A

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

biol3048 (18 decks)

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