Lecture 6- Parkinson's Disease

Question 1

PD, epidemiology

Answer 1

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

Question 2

mean age onset and duration

Answer 2

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

Question 3

for diagnosis of PD

Answer 3

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

Question 4

other motor symptoms

Answer 4

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

Question 5

non-motor symptoms

Answer 5

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

Question 6

PDD

Answer 6

PD dementia

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

Question 7

DLB

Answer 7

dementia with lewy bodies

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

Question 8

familial PD

Answer 8

autosomal dominant or recessive

Question 9

risk factors for PD

Answer 9

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

Question 10

parkin gene

Answer 10

SN degeneration, LBs absent in majority, recessive

onset 10-50yrs

Question 11

PINK-1 gene

Answer 11

LB pathology, recessive

onset 30-50yrs

Question 12

DJ-1 gene

Answer 12

diffuse LB pathology, recessive

onset 20-40yrs

Question 13

LRRK2

Answer 13

usually find LBs, dominant

onset 30-50yrs

Question 14

substantia nigra pathology in PD

Answer 14

severe loss of SN dopaminergic neurons in midbrain

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

Question 15

function of SN

Answer 15

controls voluntary movement, produces neurotransmitter dopamine

Question 16

location of SN

Answer 16

midbrain region of brain, part of basal ganglia

Question 17

basal ganglia

Answer 17

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

Question 18

role of striatum

Answer 18

planning and modulation of movement pathway

Question 19

pathology of striatum in PD

Answer 19

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

Question 20

targeting dopamine for treatments

Answer 20

L-dopa
MAO-B inhibitors
dopamine agonists

Question 21

L-dopa

Answer 21

dopamine precursor

- can cross BBB, increase dopamine levels

Question 22

MAO-B inhibitors

Answer 22

allows dopamine to accumulate in surviving neurons

Question 23

MAO-B

Answer 23

enzyme that breaks down dopamine

Question 24

dopamine agonists

Answer 24

mimics role of dopamine in brain

Question 25

Lewy bodies in non-symptomatic individuals

Answer 25

5-20% >60yrs, normal - in absence of neuronal loss and gliosis - may represent pre-clinical cases

Question 26

braak staging- proposed

Answer 26

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

Question 27

braak staging- 6 stages

Answer 27

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

Question 28

at which stage does clinical diagnosis occur

Answer 28

stage 3 of braak staging

Question 29

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

Answer 29

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

Question 30

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

Answer 30

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

Question 31

microglia in inflammation

Answer 31

mildly activated glia necessary for normal brain function | -dying neurons activate microglia, kill neurons

Question 32

alpha-synuclein 3 components

Answer 32

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

Question 33

characteristics of Alpha synuclein

Answer 33

natively unfolded protein- doesnt have secondary structure - linked to learning, development and synaptic plasticity associated with vesicles - possible regulator of dopamine release, vesicular transport

Question 34

genetic modulating factors for alpha synuclein aggregation

Answer 34

mutations in alpha synuclein | overexpression via copy number variation

Question 35

exposure to which factors promote alpha synuclein aggregation?

Answer 35

iron, oxidants, nitration, environmental toxins

Question 36

alpha synuclein and dopamine- ON PATHWAY

Answer 36

ThT positive insoluble alpha synuclein fibrils are formed

Question 37

alpha synuclein and dopamine- OFF PATHWAY

Answer 37

ThT negative soluble alpha synuclein ogligomers are formed

Question 38

how is alpha synuclein altered by dopamine?

Answer 38

dopamine oxidises the methionine residues ,makes it a soluble aggregate

Question 39

are dopamine induced oligomers toxic?

Answer 39

not sure

Question 40

alpha synuclein and membrane pore

Answer 40

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

Question 41

alpha synuclein and MMP

Answer 41

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

Question 42

alpha synuclein and mitochondria

Answer 42

increase in mitophagy

Question 43

which PD genes inhibit mitochondrial fragmentation?

Answer 43

PINK1 and Parkin- regulate and maintain mitochondria integrity

Question 44

ubiquitin proteasome system

Answer 44

involved in removing misfolded proteins | - breakdown, therefore aggregates

Question 45

parkin mutation effect

Answer 45

impaired ubiquitin ligase function

Question 46

PINK1 mutation effect

Answer 46

impaired translocation of Parkin to mitochondria

Question 47

DJ1 mutation effect

Answer 47

oxidative stress-->mitochondrial dysfunction

Question 48

LRRK2 mutation effect

Answer 48

increase kinase activity-->dopaminergic cell death

Question 49

transgenic async A53T mice

Answer 49

with prion protein promoter - high level of async, aggregated forms - motor deficit- disease causing

Question 50

6-hydroxydopamine mouse model of PD

Answer 50

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

Question 51

MPTP mouse model of PD

Answer 51

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