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354: Pathobiology > 2. Parkinson's Disease > Flashcards

2. Parkinson's Disease Flashcards

1
Q

who first described PD

A

James parkinson
- described it as a shaking palsy

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2
Q

what is the mean age of onset

A

65 years

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3
Q

what percentage of people are diagnosed before the age of 40

A

4%

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4
Q

how many people does PD affect worldwide

A

10 million

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5
Q

describe the clinical features of PD

A

rigidity
bradykinesia
tremor at rest
impaired gait
mask-like face
cramped handwriting

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6
Q

what are the pathological features of PD

A

degeneration of DA neurons in the substantial nigra or caudate-putamen

presence of Lewy bodies

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7
Q

what are Lewy bodies composed of

A

aggregated alpha-synucleiun protein

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8
Q

where are Lewy bodies found

A

in the cell body and axons of neurons in the basal ganglia

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9
Q

what dark substance from the substantia nigra is lost in PD

A

neuromelanin

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10
Q

what is the difference between PD and dementia with lewy bodies

A

in DLB - cognitive symptoms appear either at the same time or before the onset of motor problems

in PD- motor problems arise at least a year before cognitive symptom

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11
Q

what is the direct pathway of the motor circuit responsible for

A

increased movement

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12
Q

describe the processes occurring in the direct pathway:

A
  1. motor cortex releases excitatory glutamate into the caudate putamen

1b. substantia nigra releases dopamine to the caudate putamen, it stimulates the caudate pathway

  1. caudate putamen releases GABA to the substantial nigra and globus pallidus
  2. GABA binding to the globus pallidus and substantial nigra means less GABA is released to the thalamus
  3. this means glutamatergic neurons of the thalamus can fire and stimulate increased movement
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13
Q

what does dopamine bind to in the caudate putamen

A

d1 receptors

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14
Q

what additional structure is featured in the indirect pathway

A

the sub thalamic nucleus

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15
Q

describe the indirect pathway of motor movement.

A
  1. glutamate release from the motor cortex
  2. GABA is released from the caudate putamen to the globus pallidus. this creates an internal feedback within the globus pallidus whereby the pars internal and subthalamic nucleus are disinhibited
  3. glutamate release from the sub thalamic nucleus to the substantia nigra and the pars interna of the globus pallidus
  4. increases the GABA release from the globus pallidus and substantia nigra to the thalamus = decreased activation of the motor cortex
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16
Q

what happens when the substantia nigra releases dopamine in the indirect pathway

A

binds to D2 receptors to inhibit the caudate pathway
GABA neurons are inhibited - and less GABA is released onto the thalamus = increased movement

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17
Q

what happens to the direct and indirect pathways in PD

A

there is a loss of dopamine - this shifts the balance towards the indirect pathway, where stronger inhibition of the system reduces voluntary movement

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18
Q

name 3 non-modifiable risk factors for PD

A

age
sex
genetics

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19
Q

what is the sex ration for PD

A

male bias
male to female = 1.5:1

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20
Q

what percentage of cases does genetics account for

A

~10%

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21
Q

how many regions does alpha-synuclein protein have

A

3

22
Q

what are the 3 regions of a-synuclein

A
  1. ampiphatic region
  2. the non-amyloid component
  3. acidic tail
23
Q

which region is associated with familial PD

A

the ampiphatic region

24
Q

which region confers aggregation properties

A

the non-amyloid component

25
Q

what mutation is a relatively common cause of autosomal dominant PD in caucasians

A

G2019S

26
Q

describe the G2019S mutation

A

elevates LRKK2 activity - a large protein kinase

27
Q

what % of cases does the g2019S mutation account for

A

4% of familial PD cases

28
Q

describe the evidence proving a role of LRKK2 in PD

A

anti-LRKK2 antibodies strongly label brainstem and cortical levy bodies

  • could play a role in alpha-synuclein and levy body formation
29
Q

what is Parkin part of

A

the ubiquitin E3 ligase complex

30
Q

what does UCH-L1 encode

A

a de-ubiquitinating enzyme

31
Q

what does a point mutation to UCH-L1 cause

A

late-onset PD
- as there is a build up of aggregating proteins

32
Q

name 2 more mutations that cause early-onset PD

A

DJ-1 and PINK1

33
Q

what is the role of DJ-1

A

a mitochondrial protein that acts as a sensor for oxidative stress

34
Q

how many DJ-1 mutations have been identified in PD

A

19

35
Q

what is the role of PINK1

A

a protein kinase that protects cells from stress-induced mitochondrial dysfunction

36
Q

how many PINk1 mutations found in PD

A

70

37
Q

what do PINk1 and DJ-1 mutations elude to?

A

the role of mitochondrial dysfunction and oxidative damage in the pathogenesis of PD

38
Q

name 3 modifiable risk factors that increase the risk of PD

A

traumatic brain injury
heavy metals
pesticides

39
Q

name 2 things that can decrease risk of PD and by what % compared to non-users

A

smoking - 60% lower compared to non-smokers

caffeine - 30% lower compared to non-caffeine drinkers

40
Q

describe the case study in 1982 where heroin users developed irreversible parkinsons

A

7 young people (aged 20-40) injected synthetic heroin containing MPTP.

this molecule crossed the blood brain barrier where it was converted into MPP+

MPP+ gets transported into DA neurons where it can impair the electron transport chain and result in cell death

41
Q

what molecule converts MPTP into MPP+

A

glial cells

42
Q

what did the 1982 heroin fiasco suggest

A

could PD be caused by an environmental trigger similar to MPTP

43
Q

describe how a 1/3 of the Chamorro tribe came to be affected by PD

A

they indirectly ingested BMAA from flying foxes who had consumed the dangerous chemical from cycad palm nuts

BMAA is a glutamate agonist - causes excitotoxicity and neurodegeneration

= deficits

44
Q

during 1915-1926, an outbreak of which disease triggers Parkinsonism in 50% of its survivors

A

encephalitis lethargica

45
Q

what is L-dopa

A

a precursor to dopamine

46
Q

why can’t you just inject dopamine into the brain

A

it cannot pass the BBB unlike L-dopa

47
Q

how long does L-dopa effects last for? why?

A

last for approx 5 years
this is because neurons are continuing to die, so the relief will only last so long

48
Q

what is the effect of administrating carbidopa

A

its is a dopa decarboxylase inhibitor - so it prevents premature conversion into dopamine

49
Q

what can also be given to inhibit dopamine degradation

A

COMT and MAO-B inhibitors

50
Q

name a non-pharmaceutical option of managing PD

A

deep brain stimulation

51
Q

describe how deep brain stimulation works in PD

A

electrode is imparted into the pars interna of the globus pallidus, this attempted to increase input to the subthalamic nucleus

(the idea is that it bypasses the substantial nigra

52
Q

name 3 drugs in the pipeline for PD

A

antioxidants
immunotherapy
inhibiting alpha-synuclein aggregation

354: Pathobiology (10 decks)

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