Cell and Genetic basis of Parkinson's

Question 1

what type of rigidity presents in parkinsons

Answer 1

axial rigidity - in neck and trunk

Question 2

what are the early non-motor features of parkinsons

Answer 2

altered sense of smell (degeneration of olfactory circuit)
REM sleep disorder (5/10 yrs before parkinsons)
constipation
depression and anxiety (because of dopamine)
blepharospasm = difficulty moving eyes, blurred vision, involuntary opening and closing of eyes

Question 3

what are the late non-motor complications associated with parkinsons

Answer 3

autonomic failure
psychosis
dementia

Question 4

what are some random parkinsons non-motor symptoms

Answer 4

falls and dizziness
fatigue
pain
speech and communication
anxiety
hallucination and delusions
memory problems

Question 5

outline parkinsons epidemiology

Answer 5

1 in 500 people in UK have pd
affects more than 1% of the population over 60
1 in 20 cases occur in people under age of 40
most cases sporadic, but inherited forms of disease account for 3%

Question 6

outline idiopathic parkinsons

Answer 6

degeneration of dopaminergic neurones in substantia nigra - motor features
presence of lewy bodies
pathological hallmark - depigmented substantia nigra

Question 7

outline why the substantia nigra is brown coloured

Answer 7

its in the midbrain, cells produce dopamine and with time dopamine oxidises to brown pigment of melanin

Question 8

how is parkinsons pathology transmitted in the body

Answer 8

alpha synuclein protein develops in gut, stress causes enteric NS changes, alpha synuclein changes and aggregates
brings in other synuclein molecules in a CASCADE effect
starts to spread into upper parts of spinal cord slowly
PRION LIKE SPREAD up to brain
dopaminergic neurons in the substantia nigra lost

Question 9

what is L-dopa

Answer 9

most effective oral medication for parkinsons
prolonged use associated with dyskinesia
surgical intervention

Question 10

what are side effects of l-dopa

Answer 10

obsessive, compulsive behaviours, confusion, hallucinations and delusions, fainting, dizziness

Question 11

what is L-dopa to dopamine

Answer 11

a precursor , converted into dopamine in dopaminergic neurones

Question 12

what causes parkinsons in the body?

Answer 12

lewy bodies (aggregated alpha synuclein) in substantia nigra cause nerve cells to die/lose input into basal ganglia = movement problem
neuronal loss with ageing
build up of protein - needs to be degraded with 26S protease but sometimes dysfunctional
neuromelanin - brown pigment, dopamine is oxidised so can produce free radicals = problem for cells mitochondrial dysfunction ROS

Question 13

what are some environmental factors which cause parkinsons disease

Answer 13

miscellaneous factors - rural living, head trauma
toxic exposure - MPTP, herbicides and pesticides, solvents (TCE)
protective agents - smoking and coffee, natural agents
infectious exposure = encephalitis lethargica

Question 14

what is the MPTP story

Answer 14

chemist made metadyne by accident when trying to make heroin to get high
in early 20s had acute parkinsons - DOPA responsive

Question 15

what actually is MPTP

Answer 15

extremely selective chemical toxin - moves straight across BBB, converted to MPP+ selectively by MPDP and MAOb (good as substrate for dopamine transporters) but selective inhibitor of mitochondrial complex I - huge electron burst, everywhere in synapses and kills of cells
SELECTIVE DEGENERATION of mitochondrial complex I to make ROS

Question 16

where does the prion like spread seem to start and what does it affect potentially

Answer 16

in the gut and affects mitochondrial metabolism - damage causes ROS snd leads to parkinsons when reaches the brain

Question 17

outline genetic factors linked to parkinsons disease

Answer 17

no major genetic factors directly linked to most sporadic parkinsons
there are specific geographic areas with high incidence of parkinsonism
1 in 25 chance if first degree relative is affected

Question 18

outline alpha synuclein mutation

Answer 18

very rare gene mutations
cause typical parkinsons
rapid course of disease- 5 years
presence of lewy bodies
point mutations in alpha synuclein or multiple copies of SNCA cause amino acid changes

Question 19

outline alpha synuclein

Answer 19

normal protein found in most nerve cells
involved in neurotransmitter vesicle recycling
abnormally folded and aggregates as lewy bodis and lewy neurites in iPD.
slightly hydrophobic
aggregation in prion like manner

Question 20

outline alpha synuclein in mitochondria

Answer 20

overexpressing alpha synuclein in a cell shows mitochondrial clumping - becomes abnormal and dysfunctional

Question 21

outline proteasomal metabolism - removal of aged proteins

Answer 21

get rid through 26S proteasome
ubiquitin ligase take small protein ubiquitin - detects through substrate if protein has become aged, dysfunctional or oxidised
put on ubiquitin chains recognised by proteasome
substrate starts to degreade protein
aa or short peptide chains come out
mutation creates problems - instead of protein being degraded, it accumulates and oligomers form

Question 22

what other genes are associated with parkinsons

Answer 22

PARKIN
PINK1
DJ1
LRRK2
GBA
ATP13A2

Question 23

outline parkin

Answer 23

autosomal recessive
early onset, slow progression
loss of function mutation
loss of parkin leads to parkinsonism
parkin acts as a ubiquitin E3 ligase, put ubiquitin on proteins to target them for degradation
cytosolic location - translocates to damaged mitochondria

Question 24

what did mice studies show when parkin was mutated

Answer 24

Parkin -/- mice showed structurally normal mitochondria and no loss of dopaminergic neurons
but altered mitochondria number, proteins and function and synaptic transmission was impaired

Question 25

outline PINK1 gene

Answer 25

Pten Induced Kinase 1
autosomal recessive mostly
loss of function mutations
typical parkinsonism phenotype, slow progression of disease, sustained response to L-dopa, Lewy bodies
28 pathogenic mutations to date
makes mitochondria clump

Question 26

what do mice studies show about PINK1 gene

Answer 26

nothing happens in mice in terms of phenotype
doesnt lose any substantia nigra neurones, but mitochondria are abnormal and accumulate
changes in activity of mitochondrial enzymes

Question 27

how do Parkin and PINK1 interact

Answer 27

at the mitochondrial membrane
PINK1 localisation in depolarised mitochondria, on outer membrane it recruits Parkin - this relies on intact PINK1 activity
outer mitochondrial proteins are ubiquinated by Parkin/PINK1 and mitochondria then targeted for autophagy (mitophagy)

Question 28

outline the DJ-1 gene (PARK7)

Answer 28

autosomal recessive
early onset, slow progression
loss of function, point mutations
no lewy bodies
DJ1 interacts with Parkin and Pink and acts as redox sensor (detect if proteins in mitochondria are dmaaged)
stabilises mitochondria under stress
cytosolic and mitochondrial location
need DJ1 for Parkin and Pink to work

Question 29

what are PINK1, Parkin and DJ1 together?

Answer 29

a detecting, degrading , targeting system to get rid of old damaged mitochondria

Question 30

outline LRRK2 gene

Answer 30

Leucine repeat rich kinase 2
kinase - works with mitochondria to help target it with degradation and mitophagy
most common form of early onset parkinsons
autosomal dominant
rapid clinical progression with dementia
dual activity kinase and GTPase
autophagy, vesicle trafficking, mitochondrial outer membrane

Question 31

outline GBA gene

Answer 31

Gaucher’s disease (recessive)
risk factor for parkinsons when it is heterozygous (one normal one mutant)
looks like typical parkinsons
lysosomal enzyme - helps folding proteins as they move through endoplasmic reticulum
(mutation in GBA affects degradation of proteins)

Question 32

what happens when GBA is mutated

Answer 32

there is impaired localisation of misfolded glucocerebrosidase to the lysosome

Question 33

what are some SNCA turnover pathways that could be affected in Gauchers disease

Answer 33

abnormal folding of glucocerebrosidase
induction of unfolded protein response (UPS) and cell (ER) stress
protein ubiquitination
lysosomal dysfunction and decreased protein (synuclein) breakdown
abnormal membrane lipids and abnormal synuclein folding

Question 34

so what are some common cellular themes that can help us understand sporadic parkinsons disease

Answer 34

proteasome/ubiquitin
lysosome
endosome
lipids
mitochondria