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PATH30003- Frontiers in Human Disease > Lecture 6- Parkinson's Disease > Flashcards

Lecture 6- Parkinson's Disease Flashcards

1
Q

PD, epidemiology

A

2nd most common neurodegenerative disease, 1-2% of population >65 yrs

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2
Q

mean age onset and duration

A

62, range 27-85, duration 9-13 yrs, progressive

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3
Q

for diagnosis of PD

A

motor symptoms- bradykinesia + muscular rigidity/resting tremor/postural instability
-often start on one side then move to other side

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4
Q

other motor symptoms

A

body posture stooped, shuffling gait, expressionless face, freezing of movement, lacking arm swinging

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5
Q

non-motor symptoms

A

often arise prior to motor symptoms and diagnosis of PD- 60/70% of patients
cognitive- mood changes
sensory- numbness, anosmia
autonomic- constipation, hot/cold sensations

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6
Q

PDD

A

PD dementia

  • dementia occurs after PD onset
  • mean dementia onset 77 yrs
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7
Q

DLB

A

dementia with lewy bodies

  • dementia precedes or same time with PD
  • mean dementia onset 70yrs
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8
Q

familial PD

A

autosomal dominant or recessive

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9
Q

risk factors for PD

A

age, gender (M:F=3:2), higher prevalence in europe, North and south america

  • increase risk- pesticides, head injury, rural living, beta blocker use, agricultural occupation
  • decrease risk- tobacco, alcohol, coffee, NSAIDs, calcium channel blocker use
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10
Q

parkin gene

A

SN degeneration, LBs absent in majority, recessive

onset 10-50yrs

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11
Q

PINK-1 gene

A

LB pathology, recessive

onset 30-50yrs

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12
Q

DJ-1 gene

A

diffuse LB pathology, recessive

onset 20-40yrs

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13
Q

LRRK2

A

usually find LBs, dominant

onset 30-50yrs

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14
Q

substantia nigra pathology in PD

A

severe loss of SN dopaminergic neurons in midbrain

  • requires a lot of loss before see symptoms (60-70%)
  • reduced pigmentation within SN
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15
Q

function of SN

A

controls voluntary movement, produces neurotransmitter dopamine

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16
Q

location of SN

A

midbrain region of brain, part of basal ganglia

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17
Q

basal ganglia

A

collection of nuclei (cluster of neurons) in whiter matter of cerebral cortex

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18
Q

role of striatum

A

planning and modulation of movement pathway

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19
Q

pathology of striatum in PD

A

SN innervates into striatum–>basal ganglia–>motor funciton

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20
Q

targeting dopamine for treatments

A

L-dopa
MAO-B inhibitors
dopamine agonists

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21
Q

L-dopa

A

dopamine precursor

- can cross BBB, increase dopamine levels

22
Q

MAO-B inhibitors

A

allows dopamine to accumulate in surviving neurons

23
Q

MAO-B

A

enzyme that breaks down dopamine

24
Q

dopamine agonists

A

mimics role of dopamine in brain

25
Q

Lewy bodies in non-symptomatic individuals

A

5-20% >60yrs, normal

  • in absence of neuronal loss and gliosis
  • may represent pre-clinical cases
26
Q

braak staging- proposed

A

LBs accumulate before diagnosis and outside of SN , other neurotransmitters are affected not just dopaminergic

27
Q

braak staging- 6 stages

A

stage 1- vagal nerve- olfactory structures (smell)
stage 2- brain stem- responses to panic/stress
stage 3- SN, CLINICAL DIAGNOSIS, see LB- movement
stage 4- temporal mesocortex- memory and emotions
stage 5- temporal neocortex- memory, language, sensory association, premotor areas
stage 6- neocortex- sensory and motor areas

28
Q

at which stage does clinical diagnosis occur

A

stage 3 of braak staging

29
Q

describe cellular trafficking, propagation and spreading of amyloids (prion like)

A

early and late endosomes–>secrete aggregates–>end up in multivesicular bodies–>interact with bystander cells–>taken up and seeding effect–>promote further aggregation e.g. tau and tau

  • secreted protein also interact with other cell types e.g. microglia, astrocytes–>induce neuroinflammation
  • cell to cell contact- through synapse, move through different brain regions, maintain propagation
30
Q

major pro-inflammatory cytokines that are mediators of cell death in midbrain

A

TNF-alpha

IL-1Beta- induce expression from activated microglia onto dopaminergic neurons, cause neuronal deterioration

31
Q

microglia in inflammation

A

mildly activated glia necessary for normal brain function

-dying neurons activate microglia, kill neurons

32
Q

alpha-synuclein 3 components

A

N terminus- rich in basic AAs, alpha-helical formation when bound to lipids, membranes
central core- non abeta component, hydrophobic
C terminus- mainly -ve charged

33
Q

characteristics of Alpha synuclein

A

natively unfolded protein- doesnt have secondary structure

  • linked to learning, development and synaptic plasticity associated with vesicles
  • possible regulator of dopamine release, vesicular transport
34
Q

genetic modulating factors for alpha synuclein aggregation

A

mutations in alpha synuclein

overexpression via copy number variation

35
Q

exposure to which factors promote alpha synuclein aggregation?

A

iron, oxidants, nitration, environmental toxins

36
Q

alpha synuclein and dopamine- ON PATHWAY

A

ThT positive insoluble alpha synuclein fibrils are formed

37
Q

alpha synuclein and dopamine- OFF PATHWAY

A

ThT negative soluble alpha synuclein ogligomers are formed

38
Q

how is alpha synuclein altered by dopamine?

A

dopamine oxidises the methionine residues ,makes it a soluble aggregate

39
Q

are dopamine induced oligomers toxic?

A

not sure

40
Q

alpha synuclein and membrane pore

A

oligomer ring like structure integrates into transmembrane pore, disrupts integrity, calcium influx, neurotoxicity

41
Q

alpha synuclein and MMP

A

permeability transition pore -dictates the MMP

  • async interacts with different membranes in mitochondria
  • generates stress
  • oxidative stress- increased calcium, misfolded mitochondrial protein
  • OR opening of pore and breakdown of potential, decrease ATP, increase in ROS, cytoC–>apoptosis
42
Q

alpha synuclein and mitochondria

A

increase in mitophagy

43
Q

which PD genes inhibit mitochondrial fragmentation?

A

PINK1 and Parkin- regulate and maintain mitochondria integrity

44
Q

ubiquitin proteasome system

A

involved in removing misfolded proteins

- breakdown, therefore aggregates

45
Q

parkin mutation effect

A

impaired ubiquitin ligase function

46
Q

PINK1 mutation effect

A

impaired translocation of Parkin to mitochondria

47
Q

DJ1 mutation effect

A

oxidative stress–>mitochondrial dysfunction

48
Q

LRRK2 mutation effect

A

increase kinase activity–>dopaminergic cell death

49
Q

transgenic async A53T mice

A

with prion protein promoter

  • high level of async, aggregated forms
  • motor deficit- disease causing
50
Q

6-hydroxydopamine mouse model of PD

A

stable intermediate, highly toxic, induces oxidative stress

  • unilateral injection into striatum (SN terminals)–>damages terminals–>progressive cell loss of SN neurons, inflammatory response
  • decrease in staining for tyrosine hydroxylase of neurons
  • cell loss and increase in lesion size
  • motor deficits- unilateral deficit- rotational behaviour
51
Q

MPTP mouse model of PD

A

mitochondrial inhibitor

  • chronic systemic injection–>death of SN neurons, motor deficits, some LB structure
  • causes NITRATION of async (nitric stress)
  • async KO mice- resistant to MPTP
  • decrease in staining for neurons- tyrosine hydroxylase

PATH30003- Frontiers in Human Disease (20 decks)

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