Neurobiology of Disease 1 Flashcards
Describe the 2 components in the structure of a dopamine molecule. (2)
- Catechol ring with 2 hydroxyl groups
- Amine group
Dopamine shares a common backbone with which 2 other neurotransmitters? (2)
What is the collective name given to these three neurotransmitters? (1)
- Noradrenaline
- Adrenaline
Catecholamines
Name the dietary amino acid from which dopamine is synthesised. (1)
Tyrosine
Dopamine is formed from tyrosine in two steps.
Name the intermediate formed from the first reaction with tyrosine. (1)
L-DOPA
Name the enzyme which converts tyrosine to L-DOPA. (1)
Tyrosine hydroxylase (TH)
Is tyrosine hydroxylase substrate specific or non substrate specific? (1)
Substrate specific
Name an essential cofactor for tyrosine hydroxylase to convert tyrosine to DOPA. (1)
Tetrahydrobiopterin (BH4)
Describe the molecular change which occurs when tyrosine is converted to L-DOPA. (1)
Addition of a hydroxyl group
Name the enzyme which converts DOPA to dopamine. (1)
DOPA decarboxylase
Why is DOPA decarboxylase described as a non substrate specific enzyme? (1)
It can convert any L-amino acid
What is the rate-limiting step in the synthesis of dopamine? (1)
Tyrosine hydroxylase conversion
Describe the molecular change which occurs when DOPA is converted to dopamine. (1)
Removal of a carboxyl group
Describe the relative levels of DOPA in the brain. (1)
Explain why this is the case. (1)
Level of DOPA in the brain is negligible.
Because conversion of DOPA to dopamine is very rapid.
Describe ‘substrate inhibition’ of tyrosine hydroxylase. (1)
Dopamine produced from TH action is able to inhibit TH.
(More TH action leads to increased dopamine, which inhibits TH leading to decreased dopamine)
Name two ways by which dopamine synthesis may be regulated in the brain. (2)
- Neuronal activity
- Autoreceptor feedback
Describe the general effect of neuronal activity on dopamine synthesis. (1)
Describe the mechanism of this. (2)
Neuronal activity increases dopamine synthesis
- Via calcium influx
- Calcium may activate tyrosine hydroxylase
Describe the general effect of autoreceptor feedback on dopamine synthesis. (1)
Describe the mechanism of this. (3)
Autoreceptor feedback inhibits dopamine synthesis and release.
- DA binds to presynaptic D2 autoreceptors
- Decreased cAMP signalling
- Decreased voltage-gated calcium channel activation
Name the molecular change which occurs when dopamine is converted to noradrenaline. (1)
Addition of a hydroxyl group
In addition to tyrosine hydroxylase and DOPA decarboxylase, noradrenergic neurones contain what other enzyme? (1)
dopamine b-hydroxylase
Name the enzyme which converts dopamine to noradrenaline. (1)
dopamine b-hydroxylase
In addition to tyrosine hydroxylase and DOPA decarboxylase, adrenergic neurones contain what other enzymes? (2)
dopamine b-hydroxylase
PNMT
Name the enzyme which converts noradrenaline to adrenaline. (1)
PNMT
Name the molecular change which occurs when noradrenaline is converted to adrenaline. (1)
Addition of a methyl group
Name the transporter protein which facilitates reuptake of dopamine from the synaptic cleft. (1)
dopamine transporter (DAT)
Is DAT found presynaptically or postsynaptically at dopaminergic synapses? (1)
Presynaptically
How many membrane-spanning regions does the DAT protein have? (1)
12
Is DAT dependent on ATP? (1)
Explain your answer. (2)
Yes
- DAT uses sodium gradient to take up dopamine
- Sodium gradient maintained by Na/K ATPase
Is DAT an antiporter or a symporter? (1)
Symporter
Name the main method of dopamine deactivation at the synapse. (1)
Reuptake by DAT
In addition to sodium, name another ion which is taken up alongside dopamine by DAT. (1)
Chloride
A drug which inhibits DAT has what effect on dopaminergic transmission? (1)
Enhances DA neurotransmission
Give three effects on dopaminergic neurotransmission in DAT-knockout mice. (3)
- Extracellular lifetime of dopamine prolonged
- Basal extracellular levels of dopamine increased
- Intraneuronal storage of dopamine reduced
Describe the phenotype seen in striatal DAT-knockout mice. (1)
Suggest why this phenotype may be seen. (1)
Hyperactivity
May be due to compensatory changes such as receptor downregulation and gene changes resulting in reduced TH.
Name three drugs which target DAT. (3)
- Cocaine
- Amphetamine
- Methylphenidate
Name the protein which concentrates dopamine into vesicles in the nerve terminal. (1)
Vesicular monoamine transporter (VMAT)
Which form of the VMAT protein is the main protein which packages dopamine into vesicles? (1)
Name a place where a different form of this protein functions, and name the form. (2)
VMAT-2
VMAT-1 works in adrenal chromaffin cells.
The VMAT protein uses the concentration gradient of what ion to concentrate DA into synaptic vesicles? (1)
Hydrogen
Is the VMAT protein an antiporter or symporter? (1)
Antiporter
Describe how ATP is used by the VMAT protein to function as an antiporter when concentrating dopamine into synaptic vesicles. (3)
ATP used to pump protons (hydrogen ions) into vesicles
Protons then exchanged for dopamine by VMAT
So protons end up getting pumped back out of vesicles
How many membrane-spanning regions does the VMAT protein have? (1)
12
Describe the effects of reserpine on the VMAT protein, and what the resulting phenotype is. (2)
Reserpine blocks VMAT-2 and depletes DA in vesicles
resulting in a Parkinson-like phenotype.
Describe how the structure of 6-hydroxydopamine (6-OHDA) is related to that of dopamine. (1)
Same structure but with an extra hydroxyl group added to the catechol ring
Describe how 6-OHDA can interact with the DAT transporter to produce animal model of Parkinson’s disease. (3)
- DAT takes up 6-OHDA into DA neurones
- Auto-oxidation of 6-OHDA produces hydrogen peroxide
- Causes mitochondrial stress, cytochrome C release, and neuronal death
***DAT ensures 6-OHDA only kills DA neurones
Name an area of the brain where there is little DAT present. (1)
Which alternative method of dopamine inactivation is used in this area? (1)
Frontal cortex
Enzyme degradation
Name the two main enzymes involved in dopamine metabolism. (2)
Monoamine oxidase (MAO)
Catechol-O-methyl-transferase (COMT)
Where in cells is monoamine oxidase located? (1)
On the outer mitochondrial membrane
Where in cells is COMT located? (1)
Both the cytosol and bound to membranes.
Complete the sentence relating to dopamine metabolism. (1)
The two enzymes, MAO and COMT, are able to act on dopamine in either order to produce the common metabolite ……………………..
homovanillic acid (HVA)
Complete the sentence relating to dopamine metabolism. (1)
The two enzymes, MAO and COMT, are able to act on dopamine in either order to produce a common metabolite called ……………………….
If MAO acts first, the intermediate which is produced is called ………………………
If COMT acts first, the intermediate which is produced is called ………………………
Homovanillic acid
DOPAC
3-MT (3-methoxytyramine)
Describe the effect of the dopamine metabolite, HVA, on the brain. (1)
None - it is inactive and gets secreted out of the body.
Complete the following sentence relating to homovanillic acid. (1)
Brain accumulation of HVA can be measured and indirectly used as a measure of ………………………
dopaminergic activity
As well as MAO and COMT, name a third enzyme which plays a role in the metabolism of dopamine. (1)
Aldehyde dehydrogenase
Which of the following statements best describes dopamine receptors? (1)
a) all dopamine receptors are ligand-gated ion channels
b) all dopamine receptors are inotropic
c) all dopamine receptors are GPCRs
d) all dopamine receptors are excitatory
e) none of the above accurately describe all dopamine receptors
c) all dopamine receptors are GPCRs
All dopamine receptors have how many membrane-spanning segments? (1)
7
How many distinct dopamine receptors are there in the brain? (1)
5
True or false? Explain your answer if needed. (1)
All types of dopamine receptors have different distributions and functions, however the affinity of dopamine is the same for all five receptor types.
False - the different receptors have different affinities
Which dopamine receptors can be categorised as D1-like receptors?
D1
D5
Which dopamine receptors can be categorised as D2-like receptors?
D2
D3
D4
Are D1-like dopamine receptors mainly pre-synaptic or post-synaptic? (1)
Post-synaptic
Name the G protein that is coupled to G1-like receptors. (1)
Gas
Which group of dopamine receptors have large C-terminal domains? (1)
- D1-like
- D2-like
D1-like
Which group of dopamine receptors have large intracellular loop-3 domains? (1)
- D1-like
- D2-like
D2-like
Are D2-like dopamine receptors mainly pre-synaptic or post-synaptic? (1)
Both
Name the G protein which tends to be coupled to D2-like receptors. (1)
Gai
Describe the effect of activating D1-like receptors on adenylyl cyclase and cAMP. (1)
Increased AC and cAMP
Describe the effect of activating D2-like receptors on adenylyl cyclase and cAMP. (1)
Decreased AC and cAMP
Apart from effects on adenylyl cyclase and cAMP, give three other cellular effects of activating dopamine D1-like receptors. (3)
- Increased PIP hydrolysis
- Calcium mobilisation
- PKC activation
Apart from effects on adenylyl cyclase and cAMP, give two other cellular effects of activating dopamine D2-like receptors. (2)
- Increased potassium currents
- Decreased activation of voltage-gated calcium channels
Name two brain regions where D1 receptors are likely to be found. (2)
- Striatum
- Neocortex
Name two brain regions where D5 receptors are likely to be found. (2)
- Hippocampus
- Hypothalamus
Name two brain regions where D2 receptors are likely to be found. (2)
Striatum
May also be in pituitary
Name four brain regions where D4 receptors are likely to be found. (4)
- Frontal cortex
- Amygdala
- Hippocampus
- May also be found in midbrain
Where in the brain are D3 post-synaptic receptors likely to be found? (1)
Nucleus accumbens
Where in the brain are D3 pre-synaptic receptors likely to be found? (1)
Cortex
Apart from the nucleus accumbens and cortex, name two other brain regions where D3 receptors may be found. (2)
Olfactory tubercle
Hypothalamus
Suggest two methods which could be used to image and identify dopaminergic neurones. (2)
Falck-Hillarp fluorescence
Tyrosine hydroxylase immunohistochemistry
Briefly describe how dopaminergic neurones could be imaged and identified using Falck-Hillarp fluorescence. (3)
- Freeze-dried brain tissue exposed to formaldehyde
- Formaldehyde vapour converts dopamine to isoquinoline
- Isoquinoline is a fluorescent molecule seen as a yellow-green colour under microscope
Very briefly describe how tyrosine hydroxylase immunohistochemistry could be used to image and identify dopaminergic neurones. (1)
Labelled antibodies against tyrosine hydroxylase
Describe an advantage of using tyrosine hydroxylase immunohistochemistry to image and identify dopaminergic neurones as opposed to Falck-Hillarp fluorescence. (2)
TH IHC is more specific
as TH is only found in neurones and not extracellularly.
Name the four dopamine pathways in the brain. (4)
- Nigrostriatal
- Mesolimbic
- Mesocortical
- Tuberoinfundibular
True or false? Explain your answer if required. (1)
Dopaminergic cell bodies cluster in four specific regions or nuclei in the brain.
They make up about 10% of the neurones in the brain.
False - they only make up about 1% of the neurones in the brain
Briefly describe the anatomy of the nigrostriatal pathway. (2)
Substantia nigra
innervates striatum of the basal ganglia.
Describe the role of the nigrostriatal pathway in the brain. (1)
Control planning and execution of voluntary skeletal muscle movement.
Briefly describe what you would expect to see if the nigrostriatal pathway was disrupted. (1)
Parkinson’s disease and other motor symptoms
Briefly describe the anatomy of the mesolimbic dopamine pathway. (2)
VTA neurones in the midbrain
innervate the nucleus accumbens.
What are the roles of the dopaminergic mesolimbic pathway in the brain. (4)
- Emotion
- Pleasure
- Reward
- Goal-directed behaviour
Briefly describe what you would expect to see if the mesolimbic dopamine pathway was disrupted. Specifically if it is overactive. (1)
Psychosis (delusions and hallucinations)
Briefly describe the anatomy of the mesocortical dopamine pathway. (2)
VTA neurones in the midbrain
innervate the frontal cortex
Give four functions of the mesocortical dopamine pathway. (4)
- Emotion
- Motivation
- Executive functions
- Cognition
Describe what you might expect to see if there is underactivity of the mesocortical dopamine pathway. (1)
Negative symptoms of schizophrenia (social withdrawal and cognitive dysfunction)
Neuroleptic-induced deficit syndrome is a set of cognitive side effects which sometimes occur with antipsychotic drugs.
Which of the dopamine pathways in the brain may mediate this side effect profile? (1)
Mesocortical
Briefly describe the anatomy of the tuberoinfundibular dopamine pathway. (2)
DA neurones in the arcuate nucleus of the hypothalamus
innervate the median eminence in the anterior pituitary gland.
What is the function of the tuberoinfundibular dopamine pathway? (1)
Inhibit prolactin secretion
Is Huntington’s disease a neurodegenerative or a neurodevelopmental disorder? (1)
Neurodegenerative
Out of the following categories, which sets of symptoms are commonly seen in Huntington’s Disease?
a) motor
b) sensory
c) visual
d) psychiatric
e) cognitive
a) motor
d) psychiatric
e) cognitive
What is the inheritance pattern of Huntington’s Disease? (1)
Autosomal dominant
What is the prevalence of Huntington’s Disease? (1)
4-10 per 100,000
What is the peak age of onset for Huntington’s Disease? (1)
mid-life (30-50yrs)
Describe the typical progression of Huntington’s Disease. (1)
Slow progression over 20-30yrs
Complete the sentence relating to the Huntingtin gene. (2)
The Huntingtin gene is located on the ……………….. arm of chromosome …………………..
Short
4
Briefly describe the gene mutation which causes Huntington’s Disease. (1)
Too many CAG repeats in the Huntingtin gene
Which amino acid does the codon CAG code for? (1)
Glutamine
Describe the change in the amino acid sequence in the mutant Huntingtin protein. (1)
Too many glutamine residues on the protein tail
On which end of the Huntingtin gene (3’ or 5’) is the extended CAG repeat sequence found in Huntington’s disease? (1)
5’
How many CAG repeats do the normal population have in the Huntingtin gene? (1)
17-21
How many CAG repeats do people with HD usually have in the Huntingtin gene? (1)
40 or more
What is the term used to describe the phenotype produced by 36-39 CAG repeats in the Huntingtin gene? (1)
Describe this phenotype and what happens when it is passed down through generations. (2)
Reduced penetrance
Carriers may or may not develop HD
Future generations may develop HD even if carrier doesn’t
Describe the penetrance of HD in people with 40 or more CAG repeats in the Huntingtin gene. (1)
Complete penetrance
What is the term used to describe the phenotype produced by 27-35 CAG repeats in the Huntingtin gene? (1)
Describe this phenotype and what happens when it is passed down through generations. (2)
Intermediate allele
Carriers will not develop HD
Future generations may develop HD
Why may future generations develop HD, even if their ancestors only had the reduced penetrance or intermediate alleles and did not develop HD? (2)
CAG repeats are unstable and expand between generations,
so the offspring may inherit the full Huntingtin mutation.
If one parent has Huntington’s disease (and are heterozygous), what is the chance of their child developing Huntington’s disease? (1)
50%
Describe the general relationship between the length of the CAG repeat and age of onset in Huntington’s Disease. (1)
Why is this NOT predictive on an individual basis? (1)
Longer CAG repeat = lower age of onset
Other interacting genes which modify onset and phenotype may or may not be present.
Genes other than the Huntingtin gene may account for what percentage of the variability in onset in Huntington’s disease? (1)
50%
How is the onset of Huntington’s disease defined and determined? (1)
Clinical appearance of motor symptoms
In which cells is the Huntingtin protein expressed? (1)
All cells (it is ubiquitously expressed)
Where in the cells is the Huntingtin protein generally expressed? (1)
Are there any exceptions? (1)
It is mainly cytoplasmic,
however there have been some reports of nuclear localisation.
Name some physiological roles of the Huntingtin protein. (8)
- Embryonic development
- Intracellular transport
- Intracellular signalling
- Metabolism
- Neurogenesis and CNS formation
- Synaptic activity
- Transcriptional regulation
- Anti-apoptotic functions
What is the effect of knocking out the Huntingtin protein in mouse embryos? (1)
They do not survive
How does the mutant huntingtin protein become toxic to cells? (1)
Protein aggregates.
Various forms of the aggregated protein are toxic to cells.
Describe the steps of the mutant Huntingtin protein aggregating to form toxic cellular inclusions. (6)
- Monomer
- Oligomers
- Globular intermediates
- Protofibrils
- Amyloid-like fibres (beta sheets)
- Aggregates or inclusions
True or false? Explain your answer if necessary. (1)
All forms of the mutant Huntingtin aggregates are toxic to cells.
False - large aggregates or inclusions may be protective
Why has it been suggested that breaking up large mutant Huntingtin aggregates may not be beneficial in Huntington’s disease? (2)
They have been found to be protective,
perhaps because they remove the toxic intermediates.
(So breaking them up may ‘release’ toxic intermediates).
Describe the two general ‘mechanisms’ by which Huntington protein aggregates/inclusions may cause cell damage and death. (2)
- Gain of toxic functions
- Loss of normal function
Briefly describe 6 specific mechanisms by which mutant Huntingtin protein may damage cells. (6)
- Proteasome less effective at clearing mHTT
- mHTT binds to and sequesters other important cellular proteins
- Protein binding (and other factors) may lead to dysfunctional calcium signalling and homeostasis
- Protein binding (and other factors) may cause mitochondrial dysfunction
- mHTT can cause aggregates and impair BDNF transcription in nucleus
- Vesicular transport and recycling, and NT release and receptor activity affected
Describe the general change in brain weight in Huntington’s disease. (1)
10-20% reduction
Describe three specific changes in gross brain structure in HD. (3)
- Decreased striatal volume
- Decreased cortical volume
- Increased ventricle size
Describe the most prominent change in brain anatomy which occurs in HD. (1)
Loss of MSNs in the striatum
Describe the indirect basal ganglia pathway in terms of:
a) dopamine receptors on striatal MSNs
b) striatal projection onto globus pallidus
c) which cotransmitters are utilised
d) normal role in movement
(4)
a) D2 receptors
b) GABA released onto GPe
c) enkephalin
d) inhibits movement
Describe the direct basal ganglia pathway in terms of:
a) dopamine receptors on striatal MSNs
b) striatal projection onto globus pallidus
c) which cotransmitters are utilised
d) normal role in movement
(4)
a) MSNs express D1 receptors
b) GABA released onto GPi
c) substance P
d) initiates movement
Describe the effect on movement, of releasing DA onto the striatum. (1)
What is the effect of dopamine on the direct and indirect pathway? (2)
Causes movement
Activates direct pathway
Inhibits indirect pathway
Complete the sentence relating to movement and the basal ganglia. (1)
Movement is a balance between …………………………………………………..
(The answer is a phrase)
activation of the direct and indirect pathways of the basal ganglia.
In Huntington’s disease, the neurones lost in the striatum all contain what neurotransmitter? (1)
GABA
Name the subset of neurones in the striatum which are spared in Huntington’s disease. (1)
Cholinergic interneurones
Name the subset of neurones in the striatum which are lost first in Huntington’s disease. (1)
Enkephalin-containing MSNs
Name the subset of neurones in the striatum which are lost later in Huntington’s disease. (1)
Substance P-containing MSNs
Complete the sentence relating to the early stages of Huntington’s disease. (2)
In the early stages of HD, the ………………… pathway of the basal ganglia is lost, and this results in ……………… movement.
indirect
more
Complete the sentence relating to the later stages of Huntington’s disease. (2)
In the later stages of HD, the ………………… pathway of the basal ganglia is lost, and this results in ……………… movement.
direct
less
In addition to loss of enkephalin-containing MSNs in the striatum, describe another mechanism which may cause more movement in the early stages of HD. (4)
- Less DA binding to receptors in striatum due to less D2 MSNs
- Feedback mechanism causes more DA release from SNc
- Increased DA can only bind to D1 to cause more movement
- Or remaining D2 to further inhibit indirect pathway
Describe a basal ganglia loop which may be responsible for the psychiatric symptoms in HD. (4)
- Medial orbitofrontal cortex
- Nucleus accumbens
- GP/SN
- Thalamus
(then back to medial orbitofrontal cortex)
Describe a basal ganglia loop which may be responsible for the cognitive symptoms in HD. (4)
- Dorsolateral prefrontal cortex and lateral orbitofrontal cortex
- Caudate nucleus
- GP/SN
- Thalamus
(then back to frontal cortex, this can be classed as two separate loops)
With relevance to Huntington’s disease, which part of the striatum seems to be more involved in motor basal ganglia loops? (1)
Putamen
Give three early motor signs of HD. (3)
- Abnormal eye movements
- Inappropriate hand and toe movements
- General restlessness
Describe two midcourse motor symptoms of HD. (2)
- Involuntary movements (chorea)
- Hypertonic rigidity and dystonia
Describe what is meant by hypertonic rigidity and dystonia. (1)
Slow abnormal movements with increased muscle tone
Give five late stage motor symptoms of HD. (5)
Rigidity
Bradykinesia
Dystonia
Convulsions
Weight loss
Give four potential causes of death in HD. (4)
- Pneumonia
- Choking
- Chronic skin ulcers
- Nutritional deficits
True or false? Explain your answer if required. (1)
In HD, cognitive symptoms may precede motor onset by a decade or more.
True
In HD, cognitive symptoms may be described by the term ‘dysexecutive syndrome’.
Give five possible symptoms of dysexecutive syndrome. (5)
- Attention deficits
- Difficulty switching attention from one task to another
- Impaired insight and judgement
- Forgetfulness
- Language deficits
Name and describe a test which may be used to assess cognitive symptoms in HD. (2)
Stroop test
Say colour of word, not actual word
True or false? Describe you answer if needed. (1)
In HD, psychiatric symptoms generally follow a defined time course, which begins after motor onset.
False - psychiatric symptoms are highly variable over time and between patients, and may precede motor symptoms by a decade or more
Give three core psychiatric symptoms of HD. (3)
- Irritability
- Apathy
- Depression
Give three psychiatric symptoms of HD which are not core features, but are still fairly common. (3)
- Anxiety
- Disinhibition
- Obsessive/compulsive
Give two psychiatric symptoms of HD which may occur in severe cases, but which are much less common than other psychiatric symptoms. (2)
Hallucinations
Delusions
Describe the typical time course of when apathy may occur in Huntington’s disease. (1)
Gradual increase over time
Describe the typical time course of when depression may occur in Huntington’s disease. (1)
Periods of depression which come and go
Describe the typical time course of when irritability may occur in Huntington’s disease. (1)
General rise, reaching a peak, before decreasing a little.
Give four reasons why weight loss may occur in Huntington’s disease. (4)
- Involuntary movements
- Loss of appetite and motivation
- Dysphagia
- Metabolic dysfunction (potentially due to ubiquitous mHTT expression)
Give five reasons why sleep disturbance may feature in Huntington’s disease. (5)
- Circadian rhythm disturbance
- Depression
- Loss of routine
- Break-through involuntary movements
- Caffeine intake
Give three reasons which muscle weakness may feature in Huntington’s disease. (3)
- Primary muscle involvement (mHTT inclusions and mitochondrial dysfunction)
- Disuse atrophy
- Nutritional deficiencies
Give three treatment options to improve chorea in HD. (3)
Antipsychotics
Tetrabenazine
Benzodiazepines
Briefly describe why antipsychotics may be effective in treating chorea in HD. (1)
They are dopamine antagonists
Briefly describe why tetrabenazine may be effective in treating chorea in HD. (1)
It depletes dopamine and other monoamines
Briefly describe why GABA may be effective in treating chorea in HD. (1)
Enhances GABA to inhibit thalamus
Name a specific treatment (and its treatment class) for irritability in HD. (1)
Citalopram (SSRI)
How are depression and other psychiatric symptoms generally treated in HD? (1)
Using standard pharmacological agents
How are cognitive symptoms generally treated in HD? (1)
There are currently no treatments
Describe four non-pharmacological interventions which may be helpful to people with HD. (4)
- Speech therapy (including assessment of dysphagia)
- Dietician/PEG
- Physiotherapy
- Palliative care, PEG, family support in late stages
Describe the disease-modifying treatments currently available for HD. (1)
There are currently none available
Describe a potential future treatment for Huntington’s disease. (3)
siRNA or antisense oligonucleotides
to prevent translation of mHTT mRNA
so that the mutant protein is not produced
