Lecture 2: Parkinson's Disease

Question 1

What is the mean age of onset for PD?

Answer 1

60 years

Question 2

What are the clinical features of parkinsons?

Answer 2

Muscle stiffness (rigidity)
Bradykinesia
Resting tremor
Akinesia
also postural deficits, impaired gait, short shuffling steps, cramped handwriting, dementia in later stages sometimes

Question 3

What are the pathological features of PD?

Answer 3

degeneration of dopaminergic neurons in substantia nigra pars compacta and in the caudate-putamen

Question 4

What are Lewy bodies made of?

Answer 4

alpha-synuclein protein aggregates

Question 5

What is the pathological species responsible for death of dopaminergic neurons?

Answer 5

Lewy bodies (small circular bodies located intracellularly in the cell body of axons of neurons in the basal ganglia)

Question 6

What does the term Lewy body dementia refer to?

Answer 6

a broader term used to refer to both Parkinson’s disease dementia and Dementia with Lewy bodies that are both both caused by Lewy body pathological species

Question 7

What is the difference between an excitatory and inhibitory neurotransmitter?

Answer 7

Excitatory neurotransmitters will increase the likelihood of the post-synaptic neuron will fire an action potential

Inhibitory neurotransmitters will decrease the likelihood of the post-synaptic neuron will fire an action potential

Question 8

What is disinhibition?

Answer 8

Where you normally have the release of an inhibitory neurotransmitter from the pre-synaptic neuron, if you decrease the amount if inhibitory neurotransmitter being released by the pre-synaptic neuron, you will increase the likelihood of the post-synaptic neuron firing by removing the inhibition that is normally there

Question 9

Describe the basal ganglia

Answer 9

Collection of nuclei that sit in the middle of the brain (considered subcortical) and contains the caudate nucleus and the putamen that send projections down to the substantia nigra. The caudate makes connections with the subthalamic nucleus.
Also contains the nucleus accumbens and the globus pallidus

Question 10

Describe the direct motor circuit of the basal ganglia under normal conditions

Answer 10

The motor cortex releases excitatory NT glutamate into the caudate-putamen.
Stimulates GABA-ergic neurons in caudate-putamen to release GABA into the Substantia nigra pars reticulata and the Globus pallidus pars interna
Inhibits GABA-ergic neurons in Substantia nigra and Globus pallidus = less GABA released from these neurons
Disinhibition of glutametergic neurons in the thalamus = more glutamate released and stimulation of neurons in the motor cortex

Question 11

What is the main role of the direct motor circuit?

Answer 11

To promote voluntary movement

Question 12

What are the two anatomical divisions of the substantia nigra?

Answer 12

Pars compacta and the Pars reticulata

Question 13

What are the two anatomical divisions of the Globas pallidus?

Answer 13

Pars externa and the Pars interna

Question 14

What part of the basal ganglia does the motor cortex send projections to?

Answer 14

The caudate-putamen

Question 15

How does dopamine function in the direct motor circuit?

Answer 15

Substantia nigra dopaminergic neurons releases dopamine and if dopamine binds to the D1 receptors of the caudate-putamen, this excites neurons in the caudate = stimulates the direct motor circuit that leads to increased voluntary movement.

Question 16

Describe the indirect motor circuit of the basal ganglia under normal conditions

Answer 16

glutamate released from motor cortex
stimulates GABA-ergic neurons in the caudate putamen to release GABA
Inhibits GABA-ergic neurons in the Globus pallidus pars externa
Internal feedback mechanisms means there is disinhibition of the pars interna in the globus pallidus
Also disinhibition of glutamateric neurons in the subthalamic nucleus = excitatory glutamate NT released into the pars reticulata of the substantia nigra and the pars interna of the globus pallidus
This stimulates firing of GABA-ergic neurons = increased release of GABA from the Globus pallidus pars interna and Substantia nigra Pars reticulata into the thalamus
This inhibits glutamateric neurons in thalamus = decreased activation of the motor cortex and decreased movement.

Question 17

What is the role of the indirect motor circuit?

Answer 17

To modulate the direct pathway - decrease voluntary movement

Question 18

How does dopamine function in the indirect motor circuit?

Answer 18

Dopamine released from the substantia nigra dopaminergic neurons and if binds to D2 receptors in the caudate putamen
- this inhibits the GABA-ergic neurons in the caudate and ultimately increase movement by inhibiting the inhibitory indirect motor circuit.

Question 19

What is the ultimate effect of dopamine in the direct and indirect motor circuits?

Answer 19

Increased stimulation of the motor cortex and subsequently increased movement in both scenarios

Question 20

How does the loss of dopaminergic neurons in PD affect the basal ganglia motor circuits?

Answer 20

loss of dopamine input in the caudate putamen = shifts balance towards the indirect pathway leading to stronger inhibition of the system and decreased voluntary movement

Question 21

What are the non-modifiable risk factors of PD?

Answer 21

Age (mean onset 65 years)
Sex (more common in males)
Genetics (around 10% of all cases due to mutation in particular genes)

Question 22

Which genes are mutations known to cause PD and what is the inheritance pattern?

Answer 22

alpha-synuclein (autosomal dominant)
UCH-L1 (autosomal dominant)
LRKK2 (autosomal dominant)
Parkin (autosomal recessive)
DJ-1 (autosomal recessive)
PINK-1 (autosomal recessive)

Question 23

Parkin, DJ-1 and PINK-1 are what type of proteins?

Answer 23

mitochondrial proteins (tend to have early onset phenotype)

Question 24

Mutations in genes that are involved in familial cases of PD typically affect what three things?

Answer 24

1. Aggregation of alpha-synuclein
2. Proteasome (protein recycling, degradation and repair)
3. mitochondria (free radicals and oxidative stress)

Question 25

Describe the structure of the alpha-synuclein protein

Answer 25

140 amino acid protein divided into three main regions:
N-terminal Amphipathic region, NAC (non-amyloid component) domain and C-terminal acidic tail

Question 26

6 missense mutations associated with familial PD have been identified in which region of the alpha-synuclein protein?

Answer 26

the amphipathic region

Question 27

What is the function of the NAC domain of alpha-synnuclein?

Answer 27

associated with increased fibril formation - thought to confer aggregation properties

Question 28

What is LARRK2 and what are its proposed functions within the cell?

Answer 28

Leucine-rich repeat kinase 2 is a large protein kinase that contains 5 consecutive domains of leucine-rich repeats
It is thought to have a number of roles from microtubule dynamics, mitochondrial function, ubiquitin proteasome alterations and phosphorylation

Question 29

How may mutations in Parkin and UCH-L1 lead to the development of PD?

Answer 29

Parkin is part of the ubiquitin E3 ligase complex, and Ubiquitin carboxy-terminal hydrolase 1 (UCH-L1) is involved in de-ubiquitination to recycle the ubiquitin.
–> mutations in these proteins ultimately may lead to dysfunction of the ubiquitin proteasomal system that results in the build up of aggregating proteins (alpha-synuclein)

Question 30

Which mutations cause early-onset autosomal recessive PD?

Answer 30

mutations in DJ-1 and PINK-1 proteins

Question 31

What is PINK-1?

Answer 31

PTEN-induced putative kinase 1 is a mitochondrial ser/thr kinase that protects the cell from stress-induced mitochondrial dysfunction

Question 31

What is DJ-1?

Answer 31

a mitochondrial protein that acts as a sensor for oxidative stress and is coded for by the PARK7 gene

Question 32

What do mutations DJ-1 and PINK-1 tell us about the factors that contribute to the pathogenesis of PD?

Answer 32

consistent with the hypothesis that mitochondrial dysfunction and oxidative damage contribute to pathogenesis of PD

Question 33

What are some modifiable factors that increase the risk for developing PD?

Answer 33

• traumatic brain injury
• Industrial exposure
• heavy metals (such as manganese, lead, copper)
• pesticides
• Obstrucutive sleep apnoea (maybe in women)

Question 34

What are two modifiable factors that may actually decrease the risk for developing PD?

Answer 34

Smoking
Caffeine
- due to addictive nature of the compounds that stimulate neuronal function

Question 35

How is MPTP related to Parkinsonism?

Answer 35

found that after injecting synthetic heroin that contained MPTP, 7 young people developed irreversible parkinsonism/parkinsonian features

Question 36

How does MPTP cause parkinsonism?

Answer 36

MPTP can cross the BBB and is converted to MPP+ by glial cells containing monoamine oxidase B

MPP+ is transported into dopaminergic neurons an impairs electron transport in mitochondria leading to cell damage and death

Question 37

True or false: MPTP is structurally similar to the pesticide paraquat?

Answer 37

False: MPP+ is structurally similar to the pesticide paraquat

Question 38

What activity do the organic pesticide rotenone and the fungicide maneb have in common with MPP+?

Answer 38

inhibit mitochondrial complex 1 (NADH dehydrogenase)

Question 39

What was the cause of the ALS-PD-dementia complex with parkinsonian like motor neuron disease that occurred in Guam?

Answer 39

Beta-N-methylamino-L-alanine (BMAA) found in flour from cycad palm nuts they were consuming
- DMAA is a glutamate agonist and resulted in excitotoxicity and neurodegeneration (increase calcium influx, calcium toxicity)

Biomagnification = amplification of disease by consumption of flying foxes that also consumed BMAA

Question 40

How can L-dopa administration be used in treatment of PD during the early stages?

Answer 40

L-dopa is the precursor for dopamine so is converted into dopamine by DOPA decarboxylase to help surviving neurons to make more dopamine

Question 41

What other parts of the dopamine synthesis pathway can be targeted by PD treatments?

Answer 41

Once dopamine is made is can be broken down by enzymes COMPT and MAO so these can be inhibited to prevent degradation and keep it around longer in the synapse

Question 42

How can we prevent premature conversion of L-dopa to dopamine when administered peripherally?

Answer 42

administer peripherally active DOPA DC inhibitor (carbidopa)

Question 43

Why may some patients be treated with dopamine agonists before the use of L-dopa?

Answer 43

L-dopa treatments often wear off after about 5 years (this is symptomatic treatment… not removing the pathological species) - ultimately the neurons will still continue to die

Question 44

What surgical options can be used for the treatment of PD?

Answer 44

Deep brain stimulation:
implant electrode into pars interna of globus pallidus or the subthalamic nucleus to try and bypass the substantia nigra by replacing the neuronal signal with electrodes.

Question 45

Give three potential targets of disease modifying therapies

Answer 45

• preventing aggregation of alpha-synuclein
• removing Lewy bodies (alpha-synuclein aggregates)
• replacing dopaminergic neurons