Parkinson's disease

Question 1

Loss of neurotransmitters

Answer 1

60-70% of dopamine in the striatum → loss of dark pigmentation in substantia nigra pars compacta → motor dysfunction
Substance P and enkephalins in spinal neurons and striatal interneurons → motor dysfunction
Dopamine in mesolimbic areas → psychiatric symptoms (mood changes)
Cortical noradrenaline and acetylcholine → psychiatric symptoms (cognitive loss)
Hypothalamic amines → endocrine dysfunction

Question 2

Imaging

Answer 2

PET and SPECT scans show a loss DAT expression in the striatum, suggesting a loss of presynaptic dopaminergic neurons
There is a loss of DA nerve terminals but little change in postsynaptic dopamine D2 receptors → postsynaptic neurons seem to survive

Question 3

α-synuclein

Answer 3

Intracellular protein that modulates synaptic function
Consists of 3 molecular regions: N-terminal responsible for membrane interactions, hydrophobic region relevant in aggregation, and C-terminal involved in calcium binding.
The affinity of α-synuclein for cellular membranes is Ca-dependent.
This protein alters the formation of the SNARE complex.

Question 4

α-synuclein actions at rest

Answer 4

Decreases TH phosphorylation, inhibiting DA synthesis.
Increases VMAT expression on vesicles, aiding DA sequestration.
Interacts with vesicles and SNARE proteins to prevent vesicle docking and NT release.
Mediates membrane bending during endocytosis to recycle vesicles.

Question 5

α-synuclein actions during AP

Answer 5

Rapidly disperses from the terminal following calcium influx, allowing exocytosis.
TH and AADC are disinhibited, allowing DA synthesis to replenish stores.

Question 6

α-synuclein and glutamate

Answer 6

Evidence of coexpression with the glutamate/proton exchanger VGluT1 → found in glutamatergic neurons
Over-expressing α-synuclein causes an increased concentration of glutamate inside vesicles → increased mEPPs

Question 7

α-synuclein in Parkinson’s

Answer 7

Mutations leading to hyperphosphorylation cause aggregation into Lewy bodies in the substantia nigra and locus coeruleus → loss of functional protein.
TH and AADC are disinhibited → increased DA synthesis
VMAT levels decrease
Impaired vesicular recycling → depleted vesicular pool
Results in an increase in cytosolic DA but a reduction of vesicular DA → hypodopaminergic synaptic activity
Cytosolic DA auto-oxidises → produces ROS and DA quinones → cytotoxicity
In the cortex, there is an increase in p-α-syn+ neurons → increased frequency of corticostriatal activity → hyperglutamatergic activity.
An abnormal increase in spontaneous firing activity in the dorsal striatum is seen.

Question 8

Genetics

Answer 8

see saved picture
15% of patients have a first-degree relative with PD
Familial early onset PD is rare (5% of all cases)
PARK1 and PARK4 code for SNCA (α-synuclein) - mutations cause autosomal dominant early onset PD with Lewy bodies and marked rigidity.
PARK2 codes for PRKN (Parkin), which is part of the ubiquitin proteasome - mutations cause autosomal recessive early onset PD with restricted SN cell loss and no Lewy bodies.
- Parkin is a ligase that regulates mitochondrial quality control through mitophagy and mitochondrial biogenesis
- Actions of MPTP show that mitochondrial dysfunction is involved in PD.
The PARK6 locus codes for -PINK-1 (PTEN-induced kinase-1) and mutations cause autosomal recessive forms of PD.
- PINK-1 is a mitochondrial serine/threonine protein kinase that recruits Parkin to depolarized mitochondria for mitophagy
PARK7 codes for DJ1 which is involved in cellular transformation, oxidative stress response and mitochondrial function. Inheritance is recessive.
Leucine-rich repeat kinase 2 (LRRK2) and SNCA gene mutations occur in sporadic Parkinsonism, so they are higher risk factors.

Question 9

Environmental risk factors

Answer 9

MPTP is taken up by dopaminergic neurons via DAT and converted to MPP+ by MAO-B.
MPP+ acts as a mitochondrial toxin, inhibiting complex 1
Herbicides, such as paraquat, are also taken up via DAT and cause oxidative stress.
Drugs antagonising DA receptors (neuroleptics/antipsychotics) may cause PD symptoms.

Question 10

Treatment - increasing dopamine signalling

Answer 10

L-DOPA is used with a peripheral DOPA decarboxylase inhibitor, such as carbidopa.
Dopamine produced can affect all dopaminergic pathways, causing chorea, nausea, hypotension and psychosis.
D2-like receptor agonists - Ropinirole, Bromocriptine
MAO-B or COMT inhibitors can be used in conjunction with L-DOPA or D2 agonists.
Selegiline (Deprenyl) - MAO-B inhibitor
Entacapone - COMT inhibitor
Amantadine - increases dopamine release
Adenosine A-2A receptor antagonist – approved add-on therapy with L-DOPA
*Muscarinic antagonists control tremors

Question 11

Targeting neurodegeneration

Answer 11

Foetal neuronal transplantation - stem cells may degenerate again
Nicotinic receptor agonists - promote neuronal survival
Neurotrophic immunophilins - target the immune system
Block α-synuclein aggregation using antibodies or small-molecule inhibitors