Parkinsons Flashcards
What are the steps and enzymes involved in dopamine synthesis
Tyrosine taken up into dopaminergic neuron terminals by tyrosine transporters.
Tyrosine -> Dopa by Tyrosine hydroxylase
Dopa -> Dopamine by Dopa decarboxylase.
VMAT2 -> packages into vescicles.
What three things can happen to dopamine after release into synaptic cleft?
- Re-uptaken into neuron by dopamine transporter (DAT)
- Metabolised in microglial cells-> Mono-amine oxidase / Catechol-o-methyl transferase (COMT) -> Producing DOPAC / HVA
- Taken up into a noradrenalin neuron and converted to noradrenalin by Beta-hydroxylase.
What type of neurotransmitter/hormone is dopamine?
Catecholamine - Tyrosine derivative.
Structure: Benzene ring, 2 hydroxyl groups, a single amine group.
Where in the brain is dopamine primarily produced?
Substantia nigra (pars compacta) and ventral tegmental areas.
Define Parkinson’s disease
A neurodegenerative disorder - progressive degeneration of the nigrostriatal pathway resulting in depletion of dopamine. This causes alterations in muscle activity and function
causes of parkinson’s disease
- Idiopathic
- Genetic predisposition
- Glucocerebrosidase mutation: causes impaired autophagy function i.e. cannot effectively clear dysfunctional cellular components
- Dardarin (LRRK2): most commonly assoc with autosomal dominant PD
- Parkin (PARK2): autosomal recessive PD - Post-infection: HIV, HSV, Syphillis.
5 non-motor signs of PD
- Anosmia (loss of smell)
- Orthostatic hypotension
- Urinary urgency
- Sudden onset sleep/daytime sleepiness
- Mood changes
- Constipation
why does bradykinesia/Akinesia happen in PD?
Alterations to the direct and indirect pathway now that dopamine is gone:
Direct pathway: double effect
(i) dopamine no longer exciting the striatal neurons of direct pathway. Therefore activity of direct pathway is turned down. Therefore the excitatory effect of the direct pathway on the motor cortex is turned down.
(ii) inhibitory Cholinergic interneurons within striatum are now unopposed, further turning down the direct pathway.
Indirect pathway:
(i) loss of inhibition of indirect pathway by dopamine now makes the indirect pathway more active i.e. more inhibition of the thalamus therefore less excitation of motor cortex.
(ii) inhibitory cholinergic interneurons continue to excite the indirect pathway- further contributing to the dampening of motor function.
Glutamate (excitatory) is released from neurons travelling from what part of brain involved in basal ganglia circuit?
From:
Cortex
Subthalamic n
Thalamus
GABA (inhibitory) is released from neurons travelling from where?
Striatum (putamen/caudate)
Globus pallidus
How does dopamine elicit the vomit response
Dopamine or a dopamine agonist binds the D2 receptor in chemoreceptor trigger zone in medulla. This is a Gi coupled receptor resulting in downstream signalling which results in the message being relayed to the solitary nucleus. From there the message is transmitted to the vomit centre of the medulla.
Vagus and enteric nervous system are engaged to elicit the response:
Gastric relaxation
Relaxation of esophageal sphincter
Contraction of diaphragm
Contraction of abdominal muscles.
describe the 4 components of the blood brain barrier
- Tight junctions and adherens junctions between the endothelial cells of the cerebral capillaries - prevents passage of hydrophilic molecules.
- Continuous basement membrane of capillaries (no fenestrations)
- Astrocyte foot processus projecting onto capillaries
- Pericytes
- structural support
- physical barrier
- modulate cerebral blood flow through contraction
-phagocytic function
4 things that can disrupt the BBB
- Radiation exposure
- Infection
- Hypertension
- Physical trauma
what is the structure of the brain- CSF barrier
Tight junction between ependymal cells
Pia mater
basement membrane
Fenestrated capillaries
Blood
Ependymal cells are columnar/cuboidal epithelial cells lining the ventricles and central canal.
- their apical/ciliated surface secrete and circulate CSF.
-Forms blood CSF barrier
Produces 500ml CSF a day
five functions of astrocytes
- pH balance: maintains normal pH balance in CNS through removal of excess H+ ions.
- Neurotransmitters: Synthesizes and secretes glutamate, and can uptake GABA, glutamate and ATP.
- Detoxification: can remove ammonia to prevent neurotoxicity through the glutamine-glutamate cycle -> converts it to glutamine then the glutamate and returned back to neuron.
- Signal transmission/memories/ synaptic modulation: Gap junctions allow passage of small molecules + cell-cell transmission. Partakes in long-term potentiation and in functional synaptic plasticity whereby pre-existing synapses are strengthened.
- Blood brain barrier
