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Molecular Basis Of Disease > Parkinson's Disease > Flashcards

Parkinson's Disease Flashcards

1
Q

When was Parkinson’s disease first described and by who?

A

1817 known as ‘shaking palsy’ symptoms

James Parkinson

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2
Q

What is the average age of Parkinson’s onset?

A

late 50’s

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3
Q

Parkinson’s is a movement disorder but they have multiple non-motor features. What are some of these non motor symptoms?

A

cognitive impairment
autonomic dysfunction
disorders of sleep
depression
hyposmia (impaired smell)

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4
Q

Which sex is Parkinson’s more common in?

A

males

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5
Q

What are the three main features of parkinson’s disease?

A

resting tremor
muscle rigidity
bradykinesia (slowness of movement)

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6
Q

Resting tremors is commonly the first symptom of PD. Where are these tremors most evident?

A

one hand with arms at rest
- only one as it usually is asymmetric

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7
Q

What does muscle rigidity cause in patients?

A

decreased muscle tone in both flexor and extensor muscles

stooped posture

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8
Q

Bradykinesia leads to difficult with daily activities. What are some of these activities?

A

writing
shaving
using a knife and fork
slows chewing and swallowing
eventually loss of physical movement (akinesia)

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9
Q

Shuffling is a PD symptom. What troubles does this lead to?

A

short steps with feet barely leaving the ground producing shuffling noises

small obstacles tend to trip the patient

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10
Q

Soft speech is a symptom of PD. What is soft speech?

A

speech quality tends to be soft, hoarse and monotonous

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11
Q

What symptoms usually occur in the stages before a PD diagnosis is made?

A

constipation
disrupted sleep
excessive daytime sleepiness (due to disturbed sleep)
hyposmia
depression

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12
Q

What symptoms usually occur in the early stages of a PD diagnosis?

A

bradykinesia
rigidity
tremor
pain
fatigue
mild cognitive impairment

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13
Q

What symptoms usually occur in the middle stages of a PD diagnosis?

A

uncontrolled movements
urinary symptoms
orthostatic hypotension
dementia

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14
Q

What symptoms usually occur in the advanced/ late stages of PD?

A

psychosis
dysphagia
postural instability
freezing of gait/falls

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15
Q

What area of the brain is associated with neuronal loss in PD?

A

substantia nigra

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16
Q

What are the hallmarks of PD?

A
  1. neuronal loss in substantia nigra
  2. striatal dopamine deficiency
  3. intracellular inclusions containing aggregates of alpha synuclein = lewy bodies
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17
Q

Basal ganglia is the region of the brain affected by loss of neurons. What are the parts of the basal ganglia?

A

striatum
pallidum
subthalamic nucleus
substantia nigra

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18
Q

Striatum is the largest component of the basal ganglia. It receives input from many brain areas and send them only to other parts of the basal ganglia. What is the striatum’s main function?

A

regulation of posture and muscle tone

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19
Q

Why is the substantia nigra so important in PD?

A

neurons in this area produce dopamine and send it the striatum through the nigrostriatal pathway

substantia nigra is a dark colour due to melanin

20
Q

How is dopamine release associated with PD?

A

degeneration and death of dopaminergic neurons in substantia nigra leads to striatal dopamine depletion
- leading to motor abnormalities (muscle tone and posture)

21
Q

dopamine is a neurotransmitter at highest concentration in the striatum. How is dopamine synthesised?

A

L-DOPA is synthesised from tyrosine

22
Q

There a dopamine receptors present on the postsynaptic neuron. What kind of receptors are these?

A

G coupled receptors labelled D1-D5

23
Q

Where is dopamine stored in neurons?

A

stored in:
- cytosol
- oxidised by monoamine oxidase (MAO)

24
Q

What does dopamine cause in the postsynaptic neuron?

A

changes in:
- excitability
- metabolism
- gene expression

25
Q

In regard to neuronal loss when do the PD symptoms appear?

A

symptoms appear once you lose:
- 50-60% of dopamine containing neurons in substantia nigra
AND
- 70-80% of dopamine containing striatal neurons

26
Q

Insufficient formation and and action of dopamine leads to decreased stimulation of what part of the brain?

A

motor cortex stimulated by basal ganglia

27
Q

On the interior of the skull where the substantia nigra sits what changes in patients with PD?

A

as melanin is produced from the same neurons that produce dopamine the bone is a dark colour in normal people

in PD patients there is a loss of this dark colour

28
Q

Where is alpha synuclein most abundant and what is it’s theoretical function?

A

abundant in presynaptic terminals in the membrane

may maintain a supply of synaptic vesicles and regulating the release of dopamine

29
Q

mutations in alpha synuclein causes problems with?

A

matining and controlling dopamine

30
Q

alpha synuclein is encoded by SNCA gene and mutations cause hereditary PD. What is the theory of mutated alpha synuclein relation to neurodegenerative diseases?

A

axonal degeneration (along microtubules in axon) from alpha synuclein aggregates eventually becoming obstacles for normal axonal transport

31
Q

How does alpha synuclein aggregate and how does it cause aggregation in adjacent neurons?

A

proteolytic degradation declines with age
- due to PD older age onset mutated a synuclein cannot be degraded

Causes disease progression through mutated a synuclein being released and uptaken by adjacent neurons to induce further aggregation.

32
Q

Alpha synuclein can aggregate in the mitochondria what does this cause?

A

inhibits oxidative phosphorylation through complex 1 and causes oxidative stress leading to production of ROS

33
Q

PARK2 (parkin) and PINK1 are autosomal recessive PD genes. What process are they involved in?

A

clearance of damaged mitochondria through mitophagy

34
Q

How does PARK2 and PINK1 cause mitochondrial clearance?

A
  1. PINK1 cannot be imported into damaged mito and gets stuck outside
  2. PINK1 signals PARK2 to ‘tag’ the mito to be removed
35
Q

in 1976 Barry Kidston synthesised MPPP (opioid like pethidine) and MPTP was also found in the lab. Within 3 days he began exhibiting symptoms of PD. Lewy bodies and destruction of dopaminergic neurons in substantia nigra was found at autopsy. How did these symptoms occur?

A
  1. MPTP is metabolised to MPP+ by monoamine oxidase (MAO)
  2. MPP+ inhibits complex 1 of mito respiratory chain
36
Q

in 1976 Barry Kidston synthesised MPPP (opioid like pethidine) and MPTP was also found in the lab. Within 3 days he began exhibiting symptoms of PD. Lewy bodies and destruction of dopaminergic neurons in substantia nigra was found at autopsy. How does this link mitos role in PD?

A

inhibition of the mitochondrial respiratory chain lead to PD symptoms in a young male who was not at the age of onset

37
Q

How is PD diagnosed?

A

imaging
genetic tests
cerebrospinal fluid and blood tests being developed (not currently in use)

38
Q

Using genetic testing which genes are tested?

A

PARK loci
several other genes (GBA, GCH, ADH1C, TBP, ATXN2, MAPT, GLUD2) which are identified as contributing to increased risk of sporadic forms of PD

39
Q

How is cerebrospinal fluid and blood tests being studied to diagnose PD?

A

trying to be used to detect:
- a synuclein species
- lower plasma protein levels of apolipoprotein A1 (greater severity of motor symptoms)

40
Q

L-DOPA is the gold standard treatment for PD. What is the drug called? and how does it work?

A

L-dihydroxyphenylalanine (levodopa)
- a precursor for dopamine which crosses the blood brain barrier to restore dopamine levels

41
Q

What are the consequences of using L-DOPA?

A

does not prevent continuous degeneration of nerve cells in substantia nigra

continued use can result in motor complications and involuntary movements

42
Q

Inhibitors of enzymes that clear dopamine is used as a treatment for PD. What are two examples and how does each example work?

A

catechol-O-methyltransferase inhibitors
- prevents peripheral metabolism and increases bioavailability

monoamine oxidase type B inhibitors
- prevents clearance of dopamine

43
Q

What is the positives and negatives of using dopamine agonists/mimetics as a treatment for PD?

A

longer half life and less motor complications than L-DOPA but is less effective

44
Q

How is deep brain stimulation used for L-DOPA motor complications?

A

high frequency electrical stimulation of the subthalamic nucleus

45
Q

Tim Lawrence was diagnosed at 34 years old with PD so he started L-DOPA treatment but developed dyskinesias. These stopped an hour after taking MDMA which acts at the presynaptic terminal. What does MDMA do?

A

increases serotonin (mood, sleep, appetite)
- which can help alleviate the PD symptoms
increases release of dopamine (but Tim had PD)
increases norepinephrine (increases heart rate and blood pressure)

46
Q

Tim Lawrence was diagnosed at 34 years old with PD so he started L-DOPA treatment but developed dyskinesias. These stopped an hour after taking MDMA which acts at the presynaptic terminal. However long-term MDMA use results in what?

A

damage to dopaminergic neurons (just like PD)

Molecular Basis Of Disease (17 decks)

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