Parkinson's disease Flashcards
LO
- Be familiar with the clinical symptoms of PD.
- Recognise the pathological hallmarks of PD.
- Appreciate some of the proposed mechanisms that underlie this disease.
- Be familiar with the current therapies for PD.
What is Parkinsons disease?
A Movement disorder
Who does PD affect?
3-5% of over 65 year olds
How common is PD?
2ND Most common ND disease
What are some characteristics of PD that are similar to other ND?
Misfolded proteins, templated seeding, brain atrophy, lack of clearance of misfolded proteins, neuroinflammation
HD, familial AD and PD= elderly
What are the clinical symptoms of PD?
- difficulty in initiating voluntary movement
- shuffling gait
- resting tremor
- rigidity
What are the pathological hallmarks of PD?
Loss of dopaminergic neurons
Lewy bodies present in degenerating neurons
Tell me about the pathway of the loss of dopaminergic neurons in the basal ganglia?
Alongside the substantia nigra, what else helps with the modulation of movement?
The striatum of the basal ganglia i.e, caudate nucleus and putamen
What some experimental evidence that dopaminergic neurons play a loss of motor control in PD?
What are Lewy bodies composed of?
Alpha synuclein ubiquitin
The fact they contain UQ tell the body to remove it
What are some of the causes of PD?
- Sporadic
- Genetic
- Lifestyle
Tell me about some of the sporadic casues of PD?
- Unknown cause
- Drug abuse (MPTP (early onset))
- Chemical exposure i.e., pesticides
- Personality type
Tell me about MPTP and some experimental evidence
MPTP inhibits mitochondrial function
MPTP leads to degeneration of substantial nigra
Experiment: give animal MPTP treatment. Did in monkey and found severe nerve cell loss in NMPTP- treated animals. Animals showed little movement until they received dopamine injections. Shows reliance on dopamine for movement as they were not making their own
Brain scans and autopsies on those juveniles who died with EOPD to confirm
Tell me about the chemical exposure with pesticides
Link found via epidemiological studies
Need about 80% of circuitry to die before clinical symptoms are seen
The link between personality type and parkinsons?
dopamine + anxiety/ schizophrenia , treated with L-DOPA…
What is thought to be some genetic causes of PD?
DJ-1- autosomal recessive
PINK-1- autosomal recessive
Autosomal recessive needs two copies of defective gene to get disease so effects males and females equally. Recessive= LOF mutations
Parkin- autosomal recessive- juvenile onset
Synuclein mutations- juvenile onset
There are more which have since been identified
The link between lifestyle and PD?
Envrionment factors which expose you to toxins
What are some clues towards the pathogenic mechanisms of PD?
MPTP inhibits mitochondrial complex 1, it is a toxin
DJ-1 projects against Free Radical production
PINK1 localised to mitochondria
Free Radical production –> oxidative stress
Parkin is an E3 ubiquitin-protein ligase a-syn is a substrate for parkin
Reduced capacity of UPS to clear proteins (a degradation pathway)
What do the clues towards the pathogenic mechanisms of PD suggest?
Reduced UPS activity from PD cybrids
UPS activity declines as we age- this may pre-dispose some to an accumulation of alpha-syn and therefore PD
Autophagy enhanced via rapamycin and metphormin
What does the mutant a-syn (alpha-synuclein) form?
Mutations in a-syn make it more likely to fold into fibrils; this can have many conseuqences
- fibrils can attract other proteins into them
- fill up space
- cause spatial lesions
- acquire toxin gain of functions
- less amenable to refolding by chaperones and degradation by the UPS
Alternatively, are the aggregates protective – could pre-fibrils be toxic.
You should also be able to understand what can go wrong in the brain to give rise to epilepsy
Following on from that, you should understand how anti-epileptic drugs work
and finally, you should have some idea about what properties of antiepileptic drugs to take into consideration when prescribing them to patients.
Filament –> space occupying lesions impaired chaperone activity?
Tell me the role of the chaperones
Chaperones help with misfolding of proteins to help refold. If they can’t then they target for degradation via UPS
What else can a-syn interfere with?
Trafficking
Some aspects of PD are said to act in a prion like fashion, tell me about this
prion like transmission of misfolded alpha-syn oligomer
prion-like spread of disease? (doesn’t happen in just locomotor one?)
Variants of PD. One which effects locomotor and one which effects locomotor and cognitive.
What is alpha-synuclein?
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.
Biological process: negative regulation of neur…
Cellular component: postsynapse; cytoplasm; …
Molecular function: calcium ion binding; protein …
What is the onset of events from a perturbed mitochondrial function?
Why are SN DA neurones receptive?
Dopaminergic receptors are more energetically demanding so are more vulnerable in SN, as they have a greater reliance on dopamine?
Similar structure? What do SN have that other structures don’t i.e., melanin?
Outline some PD therapies
- Enhance dopaminergic transmission
- Deep brain stimulation
- Disease modifying strategies
What are some therapies to enhance dopaminergic transmission?
What may be some drawbacks to these therapies?
Drawbacks:
Side effects
Cells will still die so just boosting their function whilt they remain
Tell me about the therapy of deep brain stimulation and some pros and cons to this therapy?
Stimulate SN via artificial circuit when tremors occur
Good= pseudo circuit so doesn’t matter as much if all cells die
Bad= specialist surgeons as serious consequences, expensive, will it have other detrimental effects? This is a transient relief for rigidity, tremor, doesn’t provide recovery of circuit loss just helps alleviate symptoms
Tell me some disease modifying strategies for arresting the neurodegeneration in PD
Anti-aggregation agents
Neuroprotective agents: antioxidants, a/inflame, neurotrophic factors
Clear lewy bodies: PD vaccine (anti- alpha-syn)
Agents to promote vesicular trafficking
Cell transplantation –> successful in animals with stem cells (how do you stop stem cells forming a tumour)
Prevent transmission of oligomers
Are these strategies for PD good enough?
Are these strategies good enough?
What would their long-term side effects be?
Wearing off (dopaminergic enhancers)
Hypersensitivity
Infections (pacemaker)
Arresting neurodegeneration or postponing it?
Summary
- Know that PD is characterised by locomotor impairments
- Know that lewy bodies and loss of dopaminergic neurones in the substantia nigra are the pathological hallmarks
- Be familiar with the postulated sporadic and known familial causes of PD.
- Appreciate that oxidative stress, accumulation of a-syn filaments, compromised UPS and defective vesicular trafficking are all proposed pathogenic mechansims.
- Understand the current therapeutic interventions
Give an examle of an experimental mode of parkinsonism of laboratory animals and what paper was it discussed in?
Triarhou (2000-2013)
- The injection of 6-hydroxydopamine (6-OHDA) into midbrain of rats an mice
- causes acute degeneration of dopaminergic neurons
- 6-OHDA recognised by nigral neurons as dopamine and is taken up into cell
- enters the cytoplasm
- 6-OHDA expresses toxicity and destroys monoaminergic cells selectively
Give an experimental example that showed MPTP toxic effect, what paper was it in?
Triarhou (2000-2013)
- MPTP is a toxin that causes PD in humans
- MPTP molecule is selectively neurotoxic for human and nonhuman primates
- used to induce PD in monkeys
- in vitro, has shown that once in the cell MPTP becomes oxidised to MPP though the action of monoaminooxidade B
- MPP is the form that is toxic to dopaminergic neurons
