Parkinsons Disease Flashcards
Similarities of chronic neurodegenerative disease
Clear symptoms that is to do with the circuits impacted
Symptoms progress over time
Misfolded and aggregation of proteins
They aren’t diseases of young people but can have early onset versions
Why is the older brain more vulnerable
Exposure to environmental stressors which accumulated over time
Surveillance machinery which look for misfolded proteins worn out
What is PD and who does it affect
Movement disorder
Affects the elderly usually (3-5% of over 65s)
Second most common neurodegenerative disease after AD
Clinical symptoms of PD
Movement disorder
Difficult in initiating voluntary movement
Shuffling gait
Resting tremor
Rigidity
What gives rise to the symptoms of PD (biological)
Loss of dopaminergic neurones in substrantia nigra
Less modification = less control
Symptoms only seen when 80% of neurones dead
Evidence that loss of substantia nigra neurones cause the symptoms
Lesion the substantia nigra
Electrodes into animal brain
Complete lesion - 40% TH cells
Incomplete lesion - 60% TH cells
Sham lesion - 100% TH cells
Rotarod, open field tests
Remaining neurones in PD
Lewy bodies in degenerating neurones
Misfolded and aggregated alpha synuclein and ubiquitin
What does having ubiquitin imply
Targeted for degredation
But removal mechanisms insufficient as not removed
What are the sporadic causes of PD
unknown causes, drug abuse (MPTP), chemical exposure (pesticides), personality type
What are the genetic causes of PD
DJ-1 autosomal recessive, PINK-1 autosomal recessive, Parkin autosomal rec (juvenile onset), synuclein mutations (juvenile onset)
What experiment could test that MPTP could cause PD symptoms?
Inject MPTP into monkeys
Recreate drug context
Normal: normal cells, light active, dark rest
MPTP: reduction in substantia nigra dopermenergic cells, given dopamine increases activity
How could pesticides and PD be tested?
People who worked with pesticides/ near pesticides had higher prevalence of PD - epistemological studies
Rotenburg - nigra toxin
Fed to fruit fly, decreased doperminergic neurones compared to control in dose dependent study
Locomotion affected, could not climb chamber
How are personality types more likely to get Parkinson’s disease
Reclusive personality types
Epidemiological studies/ what’s common between those who have PD
Depression related? - setotrnergic and adrenergic systems?
How could you test depression cause of PD
Imaging to see if people with depression to see if there is substantia nigra loss (post mortem if after death)
Give PD patients who were reclusive round of antidepressants to see if there is an improvement (recycling drug)
Excessive free radicals and oxidative stress mechanism causing doperminergic neurones to die (mutations)
MPTP inhibits mitochondrial complex 1
DJ-1 protects against FR production
PINK localised to mitochondria
(THESE ARE GENETIC FACTORS)
Why are only the mitochondria in the substantia nigra effected by FR there?
Unknown but ideas:
Mitochondrial usage and energy demands are very high so more free radicals potentially produced quicker and not cleaned up so accumulate compared to others where slowly accumulate and can clear up FR
Antioxidant capacities lower there
Could test this in animal models
Reduced capacity of UPS to clear prns
Parkin is an E3 ubiquitin-prn locate
A-syn is a substrate for Parkin
Ubiquitin system dysfunctional in Parkin so accumulation - a-syn accumulation could be toxic (reduced UPS from PD cybrids)
Occupying function space of PD
Mutant a-syn readily forms filaments
Blockage
A-syn interferes with trafficking
Prion like spread of disease of PD
Prion like transmission of misfolded alpha-syn oligomer
Took lysate from patients and inject into rodent - spread in other regions and not just injection site
BUT in PD will only have pathology in substantial nigra so not actually doing it in PD patients
Summary of pathogenic mechanisms of PD
Perturbed mitochondrial function, free radicals and oxidative stress
Reduced capacity of UPS, inadequate clearance of misfolded prns, accumulation of misfolded prns
Increased aggregation of a-syn, filaments, space occupying lesions
Disruptions of vesicular transport
Why are SN DA neurones most receptive?
High energetic demands
Not as much protective antioxidant capacities to match high demand
PD therapies replacing or increasing dopamine
Compensate for dopamine loss by given more dopamine externally
L DOPA, selegline (decrease DA breakdown), amantidine, apomorphine (stimulate DA receptors), COMT inhibitors (other circuits impacted eg schizophrenia and hallucinations)
Deep brain stimulation, electrode, neurostimulator so excitation of circuit (invasive)
Both don’t stop neurones from dying
Disease modifying strategies of PD
Reduce aggregation (inhibitors? Antagonist action to regions that self aggregate?)
Neuro protective agents (antioxidants, anti inflammatory, neurotrophic factors)
Clear Lewy bodies (PD vaccine) (brain very immune privilege so inflammation there can cause other major issues eg meningitis)
Promote cesicular trafficking
Cell transplantation (stem cells into SN region and encouraged into nigra neurones but don’t have means to tell those cells to stop so could become cancerous, thing that killed in the first place may still be there and do it again)
Prevent transmission of oligomers
