Parkinsons disease Flashcards
What are the three main features of parkinsons disease?
- Resting tremor
- Muscle rigidty
- Bradykinesia (slowness of movement)
What are some physical features of parkinson’s disease?
-Gait and posture disturbances
- Shuffling
- Speech and swallowing disturbances
-Soft speech
What does muscle rigidity cause in patients?
decreased muscle tone in both flexor and extensor muscles
stooped posture
What symptoms usually occur in the stages before a PD diagnosis is made?
constipation
disrupted sleep
excessive daytime sleepiness (due to disturbed sleep)
hyposmia
depression
What area of the brain is associated with neuronal loss in PD?
Substantia nigra
What are the hallmarks of PD?
- Neuronal loss in the substantia
nigra - Striatal dopamine deficiency
- intracellular inclusions
containing aggregates of aplha‐
synuclein
= Lewy bodies
Basal ganglia is the region of the brain affected by loss of neurons. What are the parts of the basal ganglia?
striatum
pallidum
subthalamic nucleus
substantia nigra
Striatum is the largest component of the basal ganglia. It receives input from many brain areas and send them only to other parts of the basal ganglia. What is the striatum’s main function?
regulation of posture and muscle tone
Why is the substantia nigra so important in PD?
neurons in this area produce dopamine and send it the striatum through the nigrostriatal pathway
substantia nigra is a dark colour due to melanin
How is dopamine release associated with PD?
degeneration and death of dopaminergic neurons in substantia nigra leads to striatal dopamine depletion
- leading to motor abnormalities (muscle tone and posture)
dopamine is a neurotransmitter at highest concentration in the striatum. How is dopamine synthesised?
synthesised from tyrosine
There a dopamine receptors present on the postsynaptic neuron. What kind of receptors are these?
G coupled receptors labelled D1-5
Where is dopamine stored in neurons?
stored in:
- cytosol
- oxidised by monoamine oxidase (MAO)
What does dopamine cause in the postsynaptic neuron?
changes in:
- excitability
- metabolism
- gene expression
In regard to neuronal loss when do the PD symptoms appear?
symptoms appear once you lose:
- 50-60% of dopamine containing neurons in substantia nigra
AND
- 70-80% of dopamine containing striatal neurons
Insufficient formation and and action of dopamine leads to decreased stimulation of what part of the brain?
motor cortex stimulated by basal ganglia
On the interior of the skull where the substantia nigra sits what changes in patients with PD?
as melanin is produced from the same neurons that produce dopamine the bone is a dark colour in normal people
in PD patients there is a loss of this dark colour
Where is alpha synuclein most abundant and what is it’s theoretical function
abundant in presynaptic terminals in the membrane
may maintain a supply of synaptic vesicles and regulating the release of dopamine
mutations in alpha synuclein causes problems with?
matining and controlling dopamine
alpha synuclein is encoded by SNCA gene and mutations cause hereditary PD. What is the theory of mutated alpha synuclein relation to neurodegenerative diseases?
axonal degeneration (along microtubules in axon) from alpha synuclein aggregates eventually becoming obstacles for normal axonal transport
How does alpha synuclein aggregate and how does it cause aggregation in adjacent neurons?
proteolytic degradation declines with age
- due to PD older age onset mutated a synuclein cannot be degraded
Causes disease progression through mutated a synuclein being released and uptaken by adjacent neurons to induce further aggregation.
Alpha synuclein can aggregate in the mitochondria what does this cause?
inhibits oxidative phosphorylation through complex 1 and causes oxidative stress leading to production of ROS
PARK2 (parkin) and PINK1 are autosomal recessive PD genes. What process are they involved in?
Involved in the clearance of damaged mitochondria through mitophagy
How does PARK2 and PINK1 cause mitochondrial clearance?
-PINK1 cannot be imported into damaged mito and gets stuck outside
-PINK1 signals PARK2 to ‘tag’ the mito to be removed
in 1976 Barry Kidston synthesised MPPP (opioid like pethidine) and MPTP was also found in the lab. Within 3 days he began exhibiting symptoms of PD. Lewy bodies and destruction of dopaminergic neurons in substantia nigra was found at autopsy. How did these symptoms occur?
MPTP is metabolised to MPP+ by monoamine oxidase (MAO)
MPP+ inhibits complex 1 of mito respiratory chain
in 1976 Barry Kidston synthesised MPPP (opioid like pethidine) and MPTP was also found in the lab. Within 3 days he began exhibiting symptoms of PD. Lewy bodies and destruction of dopaminergic neurons in substantia nigra was found at autopsy. How does this link mitos role in PD?
inhibition of the mitochondrial respiratory chain lead to PD symptoms in a young male who was not at the age of onset
How is PD diagnosed?
imaging
genetic tests
cerebrospinal fluid and blood tests being developed (not currently in use)
Using genetic testing which genes are tested?
PARK loci
several other genes (GBA, GCH, ADH1C, TBP, ATXN2, MAPT, GLUD2) which are identified as contributing to increased risk of sporadic forms of PD
How is cerebrospinal fluid and blood tests being studied to diagnose PD?
-A-synuclein species
- Lower plasma levels of apoliprotein A1= greater severity of motor symptom
How is cerebrospinal fluid and blood tests being studied to diagnose PD?
L-dihydroxyphenylalanine (levodopa)
- a precursor for dopamine which crosses the blood brain barrier to restore dopamine levels
What are the consequences of using L-DOPA?
does not prevent continuous degeneration of nerve cells in substantia nigra
continued use can result in motor complications and involuntary movements
Inhibitors of enzymes that clear dopamine is used as a treatment for PD. What are two examples and how does each example work?
catechol-O-methyltransferase inhibitors
- prevents peripheral metabolism and increases bioavailability
monoamine oxidase type B inhibitors
- prevents clearance of dopamine
What is the positives and negatives of using dopamine agonists/mimetics as a treatment for PD?
longer half life and less motor complications than L-DOPA but is less effective
How is deep brain stimulation used for L-DOPA motor complications?
A
high frequency electrical stimulation of the subthalamic nucleus
