Cell and Genetic basis of Parkinson's Flashcards
what type of rigidity presents in parkinsons
axial rigidity - in neck and trunk
what are the early non-motor features of parkinsons
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
what are the late non-motor complications associated with parkinsons
autonomic failure
psychosis
dementia
what are some random parkinsons non-motor symptoms
falls and dizziness
fatigue
pain
speech and communication
anxiety
hallucination and delusions
memory problems
outline parkinsons epidemiology
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%
outline idiopathic parkinsons
degeneration of dopaminergic neurones in substantia nigra - motor features
presence of lewy bodies
pathological hallmark - depigmented substantia nigra
outline why the substantia nigra is brown coloured
its in the midbrain, cells produce dopamine and with time dopamine oxidises to brown pigment of melanin
how is parkinsons pathology transmitted in the body
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
what is L-dopa
most effective oral medication for parkinsons
prolonged use associated with dyskinesia
surgical intervention
what are side effects of l-dopa
obsessive, compulsive behaviours, confusion, hallucinations and delusions, fainting, dizziness
what is L-dopa to dopamine
a precursor , converted into dopamine in dopaminergic neurones
what causes parkinsons in the body?
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
what are some environmental factors which cause parkinsons disease
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
what is the MPTP story
chemist made metadyne by accident when trying to make heroin to get high
in early 20s had acute parkinsons - DOPA responsive
what actually is MPTP
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
where does the prion like spread seem to start and what does it affect potentially
in the gut and affects mitochondrial metabolism - damage causes ROS snd leads to parkinsons when reaches the brain
outline genetic factors linked to parkinsons disease
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
outline alpha synuclein mutation
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
outline alpha synuclein
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
outline alpha synuclein in mitochondria
overexpressing alpha synuclein in a cell shows mitochondrial clumping - becomes abnormal and dysfunctional
outline proteasomal metabolism - removal of aged proteins
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
what other genes are associated with parkinsons
PARKIN
PINK1
DJ1
LRRK2
GBA
ATP13A2
outline parkin
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
what did mice studies show when parkin was mutated
Parkin -/- mice showed structurally normal mitochondria and no loss of dopaminergic neurons
but altered mitochondria number, proteins and function and synaptic transmission was impaired
outline PINK1 gene
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
what do mice studies show about PINK1 gene
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
how do Parkin and PINK1 interact
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)
outline the DJ-1 gene (PARK7)
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
what are PINK1, Parkin and DJ1 together?
a detecting, degrading , targeting system to get rid of old damaged mitochondria
outline LRRK2 gene
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
outline GBA gene
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)
what happens when GBA is mutated
there is impaired localisation of misfolded glucocerebrosidase to the lysosome
what are some SNCA turnover pathways that could be affected in Gauchers disease
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
so what are some common cellular themes that can help us understand sporadic parkinsons disease
proteasome/ubiquitin
lysosome
endosome
lipids
mitochondria
