Lecture 22 - Parkinson's disease Flashcards
What is Parkinson’s disease?
Parkinson disease is neurodegenerative disorder featuring accumulation of a damaged protein.
neurodegeneraive disorder is the umbrella term for the progressive loss of structure or function of neurons including the death of neurons.
often associated with the toxic deposition of protein in the brain:
AD= amyloid beta into plaques and tau into neutrofibrillary tangles.
PD= alpha synuclein within ‘Lewy bodies’
how does neurodegeration occur?
your neurons are as old as you are and mostly don’t regenerate.
protein is misfolded due to gene mutation/ environment. there is aggregation/ deposition/ failure to clear and so synapse loss, and neurodegeneration.
what is lewy body?
Toxic alpha-synuclein aggregates found in Parkinson’s disease neurons.
what are other key molecular pathologies of Parkinson disease?
oxidative stress and mitochondrial dysfunction.
what is parkinsonism?
parkinsonism is a term used to describe a group of neurological disorders that share the same symptoms of parkinsons disease such as:
- parkinsons disease
- vascular parkinsons
- lewy body dementia
- fronto-temporal dementia
- multiple system atrophy
- progressive supranuclear palsy
what are symptoms of Parkinsonism?
a dysregualtion of motor function.
bradykinesia - slowness of movement.
tremor at rest - caused by alternative contraction of opposing muscle groups
rigidity/ freezing/ being stuck/ expressionless face
posture instability
akinesia - no normal unconscious movement (arms swinging while walking)
Hypokinesia - reduced amplitude of movement (handwriting smaller)
what is the mean age onset of Parkinsons disease?
mean age of onset 55.
repetitive ‘pill rolling’ movement
persistent tremors
shuffling gait, taking in small steps
what is the main mechanism and pathology of Parkinson disease?
central coordination of muscular movement involves various loops and feedback systems in the brain.
the nitro-striatal connection between the substantial nigra(midbrain) and striatum is key.
dopaminergic neurotransmission is regulated between the substantia nigra and striatum.
In parkinsons disease, most ventral/compacta substantial nigra cells die, resulting in severe disruption of these pathways and disorganised muscular activity. Movement inhibition occurs more than initiation.
what does levodopa do?
in normal brain, neuroelanin pigment is safely stored waste product of dopamien oxidation seen in SN cells. in parkinsons disease brain, nevre terminal fail first then cells ‘die back’. 70% cell death before symptoms detected.
oral administration of the dopamine precursor levodopa acts as compensation for lack of input from SNpc.
what are other regions of the brain that can also cause degeneration in PD?
Other neurotransmitter systems and regions show some degeneration too for example, hippocampus or cortex and dementia or psychosis that sometimes accompanies late stage parkinsons disease
what are factors that may trigger Parkinson disease?
Normal dopamine metabolism
- Generates reactive oxygen species (ROS) that damage mitochondria and damaged mitochondria produce more ROS: ‘oxidative stress’
Environmental
- Toxins
- Pyridine and related compounds
Genetic variants
- Familial forms – genes identified
- Population risk – genes identified
what are environmental factors that cause Parkinson disease neurodegeneration?
1-methyl-4-phenyl-1,2,3-tetrahydropyridine (MPTP)
- Contaminant found in a batch of synthetic heroin in 1983 San Francisco – several people developed PD soon after taking it
- Similar to paraquat and other herbicides
- When given to experimental animals caused symptoms of PD and death of nigro-striatal cells (but not Lewy bodies in acute treatment)
- Now used to create mouse models of PD
- MPTP crosses blood-brain barrier and is taken up by astrocytes
- Oxidized to a toxic metabolite MPP+ by glial MAO-B
- MPP+ is taken up via DAT (dopamine transporter) into dopaminergic neurones but also may enter via binding to neuromelanin
- Inhibition of mitochondrial Complex I: increased free radical production and oxidative stress
what is also a trigger for Parkinson disease?
gut-brain axis as a trigger for PD. incorrectly folded alpha-synuclein may enter the brain via the vagus nerve. bacterial infection creates chronic inflammatory state driving brain inflammatory changes
describe the inflammation and Parkinson’s disease?
Degeneration of DA neurons in PD associated with MASSIVE microglial activity
Inflammatory trigger uncertain: may be released cell contents including LB a-synuclein aggregates?
GOOD: phagocytosis of debris and apoptotic cells and initiation of repair processes, but…
BAD: uncontrolled inflammation results in production of neurotoxic factors that worsen neurodegenerative pathology.
Increased levels of released inflammatory cytokines and NO production + recruitment of other immune cells (gliosis)
Antibodies to proteins modified by dopamine oxidation products
Use of NSAID decreases risk of developing PD by 45%
what medication is used to treat parkisnosn disease?
Levodopa (co-beneldopa [levodopa and benserazide: ‘Madopar’]and co-careldopa [levodopa and carbidopa: ‘Sinemet’])
Dopamine agonists:
* Pramipexole, Ropinirole
* Rotigotine skin patch (Neupro)
* Apomorphine
* MAO-B inhibitors (rasagiline, selegiline, safinamide)
* COMT inhibitors (entacapone, opicapone)
* Amantadine
* Anticholinergics (procyclidine, trihexyphenidyl)
