Neurobiology of Disease 8 Flashcards
Give a definition of ‘neuropeptide’. (1)
Small protein-like molecule used by neurones to communicate with each other.
True or false? Explain your answer if appropriate. (1)
Neuropeptides are solely used for neurones to communicate with other neurones.
False - they can also be used for neurones to communicate with other tissues of the body
Give six bodily processes that neuropeptides are involved in. (6)
- Analgesia
- Food intake
- Learning and memory
- Metabolism
- Reproduction
- Social behaviours
Where in the cell are neuropeptides synthesised? (2)
In the endoplasmic reticulum
and the golgi body.
Describe the pathway/mechanism of neuropeptide synthesis. (7)
Prepropeptide produced (via DNA transcription/translation)
Signal peptide cleaved
by signal peptidases
to form propeptide
Propeptide further cleaved by endo and exopeptidases
to form peptides
then peptides undergo posttranslational modifications to produce functional neuropeptides
When neuropeptides are produced, the peptide molecules have to undergo posttranslational modifications.
Give 4 examples of common posttranslational modifications which may occur. (4)
- Phosphorylation
- Glycosylation
- Sulfation
- Acetylation
Give three forms/ways that neuropeptides can signal to other cells (often relating to how far away the target cell is). (3)
- Autocrine
- Paracrine
- Endocrine
Neuropeptides can carry out autocrine signalling.
What is autocrine signalling? (1)
A neuropeptide targets the cell it was released from
Neuropeptides can carry out paracrine signalling.
What is paracrine signalling? (1)
A neuropeptide targets a nearby cell (by diffusion)
Neuropeptides can carry out endocrine signalling.
What is endocrine signalling? (1)
Neuropeptides travel in the blood stream to a target in a different part of the body.
How are neuropeptides stored in neurones? (1)
In large dense core vesicles
Neuropeptides are stored in large dense core vesicles (LDCVs) in neurones.
Name two other molecules which can be stored in LDCVs. (2)
Growth factors
Hormones
Neuropeptides are stored in large dense core vesicles (LDCVs) in neurones.
In which part of the neurone (and how far away from the active zone) are LDCVs synthesised? (2)
Cell body
Far away from active zone
Neuropeptides are stored in large dense core vesicles (LDCVs) in neurones.
From which part/s of the neurone do LDCVs release their contents? (2)
Neurone terminals
Membranes on other parts of the neurone
True or false? Explain your answer if appropriate. (1)
Neuropeptides are stored in large dense core vesicles (LDCVs) in neurones.
After they release their contents, LDCVs are recycled for repackaging of neuropeptides.
False - LDCVs are not recycled
Does a neurone typically contain more small electron translucent vesicles, or large dense core vesicles? (1)
Small electron translucent vesicles
Name the type of molecule which is stored in small electron translucent vesicles in neurones. (1)
Neurotransmitters
Pick the sentences which best describe neuropeptides.
a) they provide diffuse actions
b) they provide very localised, specific actions
c) they have slow, neuromodulatory effects
d) they have fast effects on the membrane potential
a) they provide diffuse actions
c) they have slow, neuromodulatory effects
Name five neuropeptides which are released from the hypothalamus. (5)
- Thyrotropin-releasing hormone
- Corticotrophin-releasing hormone
- Gonadotrophin-releasing hormone
- Somatostatin
- Neuropeptide Y
Give six neuropeptides which are released from the pituitary gland. (6)
- Adrenocorticotropic hormone (ACTH)
- Beta endorphin
- a-melanocyte-stimulating hormone (a-MSH)
- Thyroid stimulating hormone (TSH)
- Vasopressin
- Oxytocin
Give some examples of neuropeptides which act on the gut and brain. (10)
- Leucin enkephalin
- Enkephalin
- Substance P
- Gastrin
- Nerve growth factor
- BDNF
- Neurotensin
- Insulin
- Glucagon
Give five neuropeptides which are released from, and may act on other tissues than the gut and brain. (5)
- Angiontensin-II
- Bradykinin
- Carnosine
- Sleep peptides
- Calcitonin
Name two neuropeptides which can be classed as ‘opioid peptides’. (2)
- Enkephalins
- Endorphins
CCK is a neuropeptide which takes part in hormonal/endocrine signalling.
What is the full name of CCK? (1)
Cholecystokinin
Name a neurotransmitter which is classed as a quaternary amine. (1)
Acetylcholine
Compare the cellular locations of neuropeptide and neurotransmitter synthesis. (2)
neuropeptide - in cell body (RER and Golgi)
neurotransmitter - cytosol of neuronal terminals
Compare the precursors of neuropeptide and neurotransmitter synthesis. (2)
Neuropeptides - cleaved from larger proteins
Neurotransmitters - synthesised from amino acids
Compare the concentrations of neuropeptides and neurotransmitters synthesised and found in neurones. (2)
Neuropeptides - low concentrations
Neurotransmitters - high concentrations
Compare the locations where neuropeptides and neurotransmitters would be found in neurones. (2)
Neuropeptides - found all over the neurone (and in other tissues)
Neurotransmitters - only found in axon terminals of presynaptic neurones
Compare the storage of neuropeptides and neurotransmitters in neurones. (2)
Neuropeptides - large dense core vesicles
Neurotransmitters - small electron-translucent secretory vesicles
Compare the sizes/molecular weights of neuropeptides and neurotransmitters. (2)
Neuropeptides - large, high molecular weight
Neurotransmitters - small, low molecular weight
Compare the speed of action of neuropeptides and neurotransmitters. (2)
Neuropeptides - slow acting
Neurotransmitters - fast acting
Compare the types of receptors that neuropeptides and neurotransmitters act on. (2)
Neuropeptides - GPCRs only
Neurotransmitters - Inotropic and GPCR
Compare the types of response that neuropeptides and neurotransmitters have (eg. neuromodulatory, excitatory, inhibitory, slow, fast). (2)
Neuropeptides - slow neuromodulatory response
Neurotransmitters - fast excitatory or inhibitory response
Compare the duration of neuropeptide and neurotransmitter action. (2)
Neuropeptides - prolonged action
Neurotransmitters - short-term action
Why do neuropeptides have prolonged action at their target tissue? (1)
They are not taken back up into the neurone
Compare the types of release stimulus for neuropeptides and neurotransmitters. (2)
Neuropeptides - released with high frequency trains of APs
Neurotransmitters - released with a single AP (high or low frequency stimulus)
What is the rate of axonal streaming of neuropeptides? (1)
few cm/day
True or false? Explain your answer if necessary. (1)
Neuropeptides are usually released from the neurone with another signalling molecule (neurotransmitter or neuropeptide).
True
Describe the cytosolic calcium concentration associated with neuropeptide and neurotransmitter release. (2)
Neuropeptides - released at low calcium concentrations (slow and low calcium increase)
Neurotransmitters - released at high calcium concentrations (fast increases)
Describe the location/proximity of the site of action of neuropeptides and neurotransmitters. (2)
Neuropeptides - different site of action than their origin (diffusion)
Neurotransmitters - released in direct apposition to their target cells
Compare the inactivation/metabolism of neuropeptides and neurotransmitters. (2)
Neuropeptides - internalised via endocytosis followed by lysosomal degradation
Neurotransmitters - metabolised by specific enzymes before/after transporter reuptake
Compare the potency of neuropeptides and neurotransmitters. (2)
Neuropeptides - 1000 times more potent than NTs
Neurotransmitters - less potent when compared to neuropeptides
Compare the species conservation between neuropeptides and neurotransmitters. (2)
Neuropeptides - species differ in the amino acid sequence
Neurotransmitters - conserved across species in terms of structure and precursor amino acid
Complete the passage relating to neuropeptides and neurotransmitters. (2)
The neurotransmitters produced and released by specific neurones ………………………… (stays constant / changes) throughout the life span.
The proportion and exact neuropeptides present in each neurone …………………………. (stays constant / changes) throughout the lifespan.
stays constant
changes
Give two reasons why the proportion and exact neuropeptides present in each neurone may change. (2)
- disease
- developmental stage
True or false? Explain your answer if appropriate. (1)
The proportion and exact neuropeptides present in each neurone is highly conserved across species.
False - it varies across species
Substance P is a member of what family of neuropeptides? (1)
Tachykinins
Which was discovered first: substance P, or its receptor (NK1)? (1)
Substance P
What was the general effect of substance P thought to be on neuronal activity when it was first discovered? (1)
Reduces neuronal activity
Which tachykinin receptor does substance P bind most strongly to? (1)
NK1
Name an NK1 receptor antagonist which may reduce the effects of substance P in the body. (1)
What can NK1 receptor antagonists be used for therapeutically? (1)
Aprepitant
Used to reduce chemotherapy-induced nausea and vomiting, and other antiemetic uses.
Which is the largest family of neuropeptides? (1)
Tachykinins
Describe the variability between members of the tachykinin neuropeptide family in terms of:
a) the COOH sequence
b) the N terminal sequence
c) the middle sequence
This refers to the amino acid sequence. (3)
a) conserved between different tachykinins
b) Varies by one amino acid
c) Varies between different tachykinins
The N terminal of different members of the tachykinin neuropeptide family usually varies by one amino acid.
Why is it essential that this amino acid varies? What is it important for? (1)
Receptor activation
The N terminal of different members of the tachykinin neuropeptide family usually varies by one amino acid.
Give the common N terminal sequence, using X as the amino acid that varies. (6)
-Phe-X-Gly-Leu-Met-NH2
The N terminal of different members of the tachykinin neuropeptide family usually varies by one amino acid.
What is the criteria that the amino acid must meet to be the variable part of the N terminal? (1)
Must be hydrophobic
Give some examples of members of the tachykinin family of neuropeptides. (7)
- Substance P
- Neurokinin A
- Neurokinin B
- Neuropeptide K
- Neuropeptide Y
- Hemokinin-1
- Endokinin-A/B/C/D
Give two areas/branches of the nervous system which use neuropeptide Y as a signalling molecule. (2)
Brain (hypothalamus)
Autonomic nervous system (sympathetic)
Where is neuropeptide Y predominantly produced in the brain? (1)
Hypothalamus
Give some examples of the roles of neuropeptide Y produced in the hypothalamus. (8)
- Increased food intake
- Increased storage of energy as fat
- Decreased anxiety and stress
- Decreased voluntary alcohol intake
- Decreased blood pressure
- Decreased pain perception
- Affects circadian rhythm
- Controls epileptic seizures
In which part of the autonomic nervous system is neuropeptide Y usually produced? (1)
Sympathetic nervous system
Give two roles of neuropeptide Y in the sympathetic nervous system. (2)
- Strong vasoconstrictor
- Growth of fat tissue
Name five neuropeptide Y receptors. (5)
Which of these are found in humans? (1)
NPY1R
NPY2R
NPY4R
NPY5R
NPY6R
1, 2, 4, and 5 are found in humans
Are neuropeptide Y receptors inotropic (ion channels) or metabotropic (GPCRs)? (1)
Metabotropic (GPCRs)
The neuropeptide Y receptors are:
NPY1R, NPY2R, NPY4R, NPY5R, NPY6R
Which are excitatory, and which are inhibitory? (5)
What G proteins are they all coupled to? (5)
INHIBITORY:
1, 5, 6 - coupled to Gi
EXCITATORY:
2, 4 - coupled to Gq
The four neuropeptide Y receptors described in humans are:
NPY1, NPY2, NPY4, NPY5
Which ones are feeding stimulators, and which are appetite inhibitors? (4)
1 and 5 are feeding stimulators
2 and 4 are appetite inhibitors
As a neuromodulator, NPY is able to alter postsynaptic neuronal responses to other neurotransmitters.
Give two general alterations seen in other neurones, in terms of their response to glutamate, when NPY is present. (2)
- Evoked EPSP amplitude decreased
- Smaller glutamate-induced calcium responses in postsynaptic cells
Very briefly explain the effects of substance P on a neurone. (4)
- Potentiates NMDA receptors
- Releases endocannabinoids
- Reduces calcium currents
- Inhibits potassium channels
How does substance P potentiate NMDA receptors on neurones? (2)
Give a piece of experimental evidence for substance P potentiating NMDA channels. (1)
- Activates NK1 receptors
- Which act via protein kinase C (PKC) on NMDA channels
Substance P increases frequency of NMDA-induced oscillations in the presence of TTX.
How does substance P result in endocannabinoid release? (2)
What is the action of these released endocannabinoids? (3)
- Substance P activates NK1 receptor
- Endocannabinoids synthesised from DAG or released by Ca from internal stores
ACTION of ENDOCANNABINOIDS:
- Act as retrograde messengers
- via presynaptic CB1 receptors
- To depress glycinergic synaptic transmission
Describe how substance P can reduce calcium currents in neurones. (1)
What is the effect of this? (1)
Inhibition of N-type Cav2.2 channels
This will reduce activation of Ca-dependent K channels (KCa)
Give three effects of substance P inhibiting background K channels in a neurone. (3)
- Membrane depolarisation
- Increased membrane resistance
- Increases firing rate
Name a substance P antagonist, which may also reduce levels of substance P. (1)
Capsaicin
Name two substance P antagonists, and suggest possible clinical uses. (2)
- Capsaicin (analgesic and anti-inflammatory)
- Aprepitant (antiemetic)
Capsaicin (an analgesic and antiinflammatory drug) and aprepitant (an antiemetic drug) are substance P antagonists.
What does this information suggest about roles of substance P an how these roles are carried out? (4)
Substance P may potentiate pain
by increasing excitability of pain neurones.
Substance P may also potentiate vomiting
by increasing excitability of vomiting neurones.
Is substance P suggested to promote or impair wound healing in humans? (1)
Promotes wound healing of nonhealing ulcers in humans.
Substance P can act as a potent vasodilator.
Give another neuropeptide/neurotransmitter that this action is dependent on. (1)
Nitric oxide
True or false? Explain your answer if appropriate. (1)
BDNF is a neurotrophic factor, as well as a neuropeptide.
True
Which receptor does BDNF usually bind to on a neurone? (1)
Give three general effects of BDNF activating this receptor. (3)
TrkB receptor
- Promotes synaptic plasticity
- Promotes neuronal growth
- Promotes neuronal survival
Briefly describe the mechanism by which activation of the TrkB receptor by BDNF may cause changes within the neurone. (2)
- Initiation of various signalling cascades within the cell
- Including alteration of gene expression via CREB
Give three specific brain/development functions which may rely on BDNF signalling. (3)
HINT: these are not synaptic plasticity, neuronal growth, and neuronal survival - these are more general functions.
- LTP
- Neurogenesis
- Neuronal differentiation
What is the general effect of BDNF on neuronal activity? (1)
Increases neuronal activity
There are two active forms of the somatostatin peptide which have roles in the body.
Describe the structures of the two active forms. (2)
Short form (14 amino acids)
Long form (28 amino acids)
Describe the locations where the two different active isoforms of somatostatin work primarily in the body. (2)
Short (14aa) = brain
Long (28aa) = GI tract
Describe the relative half life of somatostatin. (1)
1 to 3 minutes
Give four general functions of the neuropeptide, somatostatin. (4)
- Motor activity
- Sleep
- Sensory activity
- Cognitive processes
Give four neurological conditions in which somatostatin may be implicated. (4)
- Alzheimer’s disease
- Parkinson’s disease
- Depression
- Schizophrenia
Name the receptors which somatostatin works at. (1)
SST receptors
Are SST receptors, which are activated by somatostatin, ion-channels or GPCRs? (1)
GPCRs
Describe the effects of somatostatin on the following cellular functions. (4)
a) hormone secretion
b) cell growth
c) proliferation
d) apoptosis
a) reduced hormone secretion
b) reduced cell growth
c) reduced proliferation
d) increased apoptosis
Name a neuropeptide which belongs to the same family as somatostatin. (1)
Cortistatin
Compare the receptor distribution of cortistatin and somatostatin receptors in the brain. (2)
Cortistatin = mainly in cortex
Somatostatin = more widespread throughout the brain
True or false? Explain your answer if necessary. (1)
Also, complete the sentence. (1)
Somatostatin receptor subtypes (eg. sst1, sst2 etc) are expressed in a ………………………….. manner throughout the brain.
This suggests that different receptor subtypes ………………….
type-specific
have different effects on neurones
What is thought to be the role of somatostatin neurones in the central amygdala? (1)
Mediating anxiety
Describe an appropriate experimental technique to test the effects of serotonin neurones in the central amygdala on anxiety? (3)
Optogenetics
Then look at behaviour on open field test
and/or elevated plus maze
Describe two findings that we would expect on the open field test when somatostatin neurones in the central amygdala are stimulated using optogenetics. (2)
- Decreased centre time
- Increased border time
Describe two findings that we would expect on the elevated plus maze when somatostatin neurones in the central amygdala are stimulated using optogenetics. (2)
- Decreased open arm time
- Increased closed arm time
Name the three most prevalent neurodegenerative disorders. (3)
- Alzheimer’s disease
- Parkinson’s disease
- Motor neurone disease
Are motor neurone disease more common in males or females? (1)
By a lot or only by a little? (1)
More common in males
But only by a little
What is the usual age of onset for motor neurone diseases? (1)
40-60yrs
Give three general symptoms which tend to apply to all motor neurone diseases. (3)
- Muscle contraction weakness
- Loss of muscle mass
- Inability to control movement
Give a sentence describing the general cause of motor neurone diseases. (1)
Progressive degeneration of motor neurones in the brain and spinal cord innervating skeletal (voluntary) muscles
What is the median survival for motor neurone diseases? (1)
4 years
Describe the most common cause of death in motor neurone disease patients. (2)
Respiratory weakness
leading to pneumonia
In the 19th century, Duchenne investigated motor neurone diseases and found that the muscle itself is actually still able to contract normally.
What does this suggest about the aetiology of motor neurone diseases? (1)
Impaired motor neurone innervation rather than muscle pathology
What is the most common type of motor neurone disease. (1)
Give an alternative name. (1)
Amyotrophic lateral sclerosis
Lou Gehrig’s disease
Which three muscle groups are affected first in ALS? (3)
- Tongue
- Hand
- Legs
Is ALS due to degeneration of upper or lower motor neurones? (1)
Both
Describe the change in ACh tone at the NMJ in ALS. (1)
Loss of ACh tone
Give three brain functions that are usually spared/preserved in ALS. (3)
- Eye movements
- Sensations
- Cognitive function
Apart from ALS, name three other motor neurone diseases. (3)
- Progressive bulbar palsy
- Progressive muscular atrophy
- Primary lateral sclerosis
After ALS, which motor neurone disease is the most common, and does it typically present earlier or later than ALS? (2)
Progressive bulbar palsy
Presents later (around 70yrs)
Describe the early symptoms of progressive bulbar palsy. (1)
Tongue wasting and fasciculation
Describe the early peripheral nervous system/spinal cord symptoms seen progressive bulbar palsy. (1)
None
Which group of motor neurones is lost in progressive bulbar palsy? (1)
Brainstem motor neurones (LMN)
Describe the typical progression rate of progressive bulbar palsy. (1)
Fast
Give two variants of progressive muscular atrophy. (2)
Flail arm
Flail leg
Which forms of motor neurone disease are rare? (2)
Progressive muscular atrophy
Primary lateral sclerosis
Describe the typical symptoms/presentation of progressive muscular atrophy. (2)
Wasting and functional disability of arms/legs
with other regions spared
Does progressive muscular atrophy involve upper or lower motor neurone degeneration? (1)
Lower
Describe the typical rate of progression of progressive muscular atrophy. (1)
Slower
Describe the symptoms seen in primary lateral sclerosis, and what symptoms are not seen. (4)
- Little/no muscle wasting
- Stiffness
- Pain
- Spasticity
(in lower limbs)
Which motor neurones (upper/lower) degenerate in primary lateral sclerosis? (1)
Upper motor neurones
Describe the typical progression seen in primary lateral sclerosis. (2)
Slowly progressive but non-fatal
May progress to ALS
Which type of motor neurone disease may feature mild cognitive changes? (1)
Primary lateral sclerosis
Kennedy’s disease (spinobulbar muscular atrophy) is similar to motor neurone disease in which ways? (2)
- Similar prevalence
- Similar symptoms
Describe the symptoms/presentation typically seen with spinobulbar muscular atrophy (Kennedy’s disease). (1)
Increasing weakness and wasting of the muscles
How is life expectancy affected by spinobulbar muscular atrophy? (1)
It is not
Is spinobulbar muscular atrophy more common in males or females? (1)
Almost exclusively affects males
Which motor neurones (and any other structures) are affected in spinobulbar muscular atrophy? (2)
Lower motor neurones
Peripheral muscles
Describe the age of onset of spinobulbar muscular atrophy compared to motor neurone disease. (1)
Early onset (about 40yrs)
Give four symptoms commonly seen in ALS. (4)
- Muscle weakness
- Muscle wasting
- Muscle stiffness
- Muscle cramps
Give six symptoms/everyday deficits experienced with ALS. (6)
- Difficulty walking
- Difficulty standing
- Difficulty with posture
- Clumsiness
- Falls
- Difficulty swallowing
True or false? Explain your answer if appropriate. (1)
People with ALS never experience cognitive deficits.
False - about 35% have mild cognitive change and 5-10% have frontotemporal dementia
Describe two types of cognitive/behavioural symptoms which are sometimes seen in ALS patients. (2)
- Mild cognitive change affecting executive functions (planning, decision-making, language)
- Frontotemporal dementia (FTD)
True or false? Explain your answer if appropriate. (1)
In ALS, symptoms and symptom progression is variable between patients. This makes the course of the disease difficult to predict.
True
Give six aspects of the clinical workup which may help to diagnose ALS. (6)
- Clinical examination
- Blood tests
- Electromyography
- Nerve conduction tests
- Transcranial magnetic stimulation
- Magnetic resonance imaging
Give a sign of ALS seen on a blood test. (1)
Why can this result not be used to confirm diagnosis? (1)
Increased levels of creatinine kinase (muscle breakdown)
Also seen in other conditions (MI, muscle injury, alcohol abuse, medications)
What is electromyography (EMG)? (1)
How can it help to confirm a diagnosis of ALS? (1)
Fine needles which record nerve impulses and reponses within certain muscles
It can detect early changes, even if muscle activity still seems normal
What are nerve conduction tests? (1)
How can they help to confirm a diagnosis of ALS? (1)
Electrical impulse applied through a small pad on the skin. Measure response.
Measures muscle compound action potential, conduction velocity, and latency.
How can transcranial magnetic stimulation be helpful to confirm a diagnosis of ALS? (1)
Can stimulate and measure threshold/response of upper motor neurones
How can MRI be useful in confirming diagnosis of ALS? (1)
Can rule out other possible explanations for symptoms
Give four criteria that should be met for a diagnosis of ALS to be made. (4)
- Both upper and lower lower motor neurone signs
- In multiple regions of the body
- Symptoms are progressive
- Symptoms are spreading to involve different regions
Give two symptoms/signs that may be seen in ALS due to brainstem/cranial motor neurone degeneration. (2)
Drooping eyelids
Impaired speech
In ALS, the corticospinal tracts may degenerate. Is this pathology more likely to cause flaccidity or spasticity in muscles? (1)
Spasticity
Give four symptoms in ALS, seen due to degeneration of the spinal a-motor neurones. (4)
- Fasciculations
- Muscle wasting
- Weakness
- Hypotonia
Give five changes which may be seen in the spinal cord or alpha-motor neurones of someone with ALS. (5)
- Smaller ventral horn
- Spheroids in ventral horn (ghost cells + filaments)
- Decreased choline acetyltransferase
- Decreased motor neurone terminal sprouting (at NMJ)
- Increased glutamate levels in CSF
Describe how motor nerve conduction velocity is usually different in people with ALS. (1)
Usually normal
According to twin studies, what is the heritability of ALS? (1)
60%
What percent of ALS cases are purely genetic? (1)
5-10%
Name two autosomal dominant gene mutations which may cause ALS. (2)
Which chromosomes are these genes on? (2)
C9orf72 gene (chromosome 9)
SOD1 (superoxide dismutase; chromosome 21)
As well as ALS, give another condition, in which 25% of cases present with mutations in the C9orf72 gene. (1)
Frontotemporal dementia (FTD)
Complete the sentence, relating to the prevalence of the C9orf72 gene mutation in ALS. (2)
The mutation is seen in 25-40% of ……………………. cases of ALS, and 7% of ………………………. cases of ALS.
familial
sporadic
Describe the C9orf72 gene mutation associated with ALS. (4)
a) in which cells is it expressed?
b) what is its normal role in cells?
c) what is the exact mutation which is implicated in ALS?
d) how is the protein affected?
a) highly expressed in motor neurones
b) influences mRNA production
c) Hexanucleotide expansion (GGGGCC), >30=ALS
d) unclear how protein is affected
Complete the sentence relating to the SOD1 gene mutation in ALS. (2)
The mutation is present in 10-15% of …………………….. cases of ALS, and 1-2% of ……………………. cases of ALS.
familial
sporadic
SOD1 mutations are seen in ALS.
What is the normal role of the superoxide dismutase protein? (3)
Anti-oxidant
which converts superoxide (O2-)
to hydrogen peroxide and oxygen.
How does the SOD1 mutation, as seen in ALS, affect the superoxide dismutase protein? (2)
Mutant SOD1 aggregates and forms clumps
and loses antioxidant function
SOD1 is a mutation seen in ALS.
Which motor neurones are affected by this mutation? (1)
All motor neurones
Give an example of an autosomal recessive gene mutation which is seen in ALS. (1)
Give the locus of this gene on the chromosome. (1)
ALS2
chromosome 2q33
ALS2 gene mutations are seen in ALS.
What protein is encoded by the ALS2 gene? (1)
Which cells is this protein present in? (1)
ALSIN protein
Present in motor neurones
ALS2 gene mutations (which encode the ALSIN protein) are seen in ALS.
What is the normal function of the ALSIN protein? (3)
- Guanine exchange factor involved in recycling of G proteins
- Involved in development of axons and dendrites
- Essential for transmission of nerve impulses
ALS2 gene mutations (which encode the ALSIN protein) are seen in ALS.
Describe the exact mutation (allele) which causes ALS. (1)
Describe the effect of a different allele on neurones. (1)
Short form causes ALS
Long form is neuroprotective
Name a gene mutation associated with an atypical late-onset form of ALS. (1)
What locus is this gene found in the genome? (1)
What is the result of this mutation on cellular function? (1)
Vesicle-associated membrane protein B
20q13.3
Dysfunction of intracellular membrane trafficking
Name a gene mutation associated with a rare, autosomal dominant form of juvenile ALS. (1)
What chromosome is this gene found on? (1)
What is the role of the protein produced by this gene? (1)
Sentaxin gene
Chromosome 9
DNA/RNA helicase controlling RNA processing
Describe how the prevalence of gene mutations in ALS changes around the world. (1)
In different areas of the world, different mutations have different prevalence.
Comparing familial cases of ALS in Europe and Asia, which region has the C9orf72 gene as the most common known mutation, and which region has SOD1 as the most common known mutation causing ALS? (2)
C9orf72 = Europe
SOD1 = Asia
Apart from SOD1 and C9orf72, give two other gene mutations which may contribute to familial (and potentially sporadic) ALS. (2)
TARDBP (TAR DNA binding protein)
FUS (fused in sarcoma)
TARDBP (TAR DNA binding protein) may be mutated in ALS.
Briefly describe it’s usual role in cells. (1)
How is the protein altered in ALS? (1)
Involved in transcription
In ALS, protein forms aggregates
FUS (fused in sarcoma) may be mutated in ALS.
Give four normal roles of the FUS protein. (4)
How is the protein altered in ALS? (1)
- RNA binding protein
- Involved in transcription
- DNA repair
- RNA splicing
In ALS, protein aggregates in motor neurones
What is the most common genetic cause/contribution of ALS? (1)
Idiopathic
What percentage of ALS cases have no family history? (1)
90%
Give four potential causes of ALS which are not due to gene mutations. (4)
- Chemical imbalance (specifically too much glutamate)
- Protein mishandling
- Disorganised immune response
- Environmental toxin exposure
Describe how high levels of glutamate may contribute to ALS pathology. (1)
High glutamate levels may cause excitotoxicity and neuronal degeneration.
Describe how protein mishandling may contribute to ALS pathology. (1)
Inability of proteins such as ubiquilin2 to repair motor neurones and clear misfolded proteins.
Describe how a disorganised immune response may be caused and contribute to the pathology of ALS. (3)
- Improper function of ubiquilin2 in protein degradation (via autophagosomes)
- Damaged proteins and ubiquilin2 build up in motor neurones
- Immune system attacks and kills healthy cells
Give four environmental toxins which may increase risk of ALS. (4)
- Metals
- Radiation
- Solvents
- Electromagnetic fields
There is a two-fold increase in ALS incidence in the military.
Give four reasons why this might be the case. (4)
- Exposure to certain chemicals or metals
- Injuries
- Viral infections
- Intense exertion
Describe an incident which can provide evidence that ALS can sometimes be due to environmental causes. (3)
High rates of amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) in Western Pacific after WWII (also known as Lytico-Bodig).
Change in prevalence, age of onset, and phenotype over time argue for an environmental cause.
Found to be due to seeds used to cook in these countries.
Describe the phenotype and symptoms seen in ALS-PDC. (2)
Slowly progressive degenerative disease
with features of ALS, Parkinsonism, and dementia.
Describe the hypothesised environmental cause of ALS-PDC in the Western Pacific after WWII. (4)
Cultures utilised cycad (palm) seeds for medicinal/food sources
Seeds contain b-methylamino-L-alanine (BMAA) which is an excitatory amino acid and neurotoxin
BMAA causes repetitive firing in rat neurones, causing excitotoxicity
And the concentration of BMAA accumulates throughout processing and cooking
How does the proposed mechanism of BMAA in cycad seeds causing ALS compare to current known causes of ALS? (2)
BMAA is excitatory amino acid causing excitotoxicity
which is similar to increased glutamate levels seen in ALS patients
Describe three pieces of evidence supporting the theory that increased incidence of ALS-PDC after WWII was due to cycad seeds and their high levels of BMAA. (3)
- Raw seeds shown to be poisonous by soaking them in water and feeding to chickens
- BMAA shown to cause repetitive firing and excitotoxicity in rat neurones
- 1 month oral treatment with BMAA causes Parkinson’s tremor in vervet monkeys
Suggest three cellular mechanisms by which motor neurones may be damaged in ALS. (3)
- Mutation/disruption of neurofilaments
- Superoxide dismutase dysfunction
- Overactivation of glutamate receptors
Briefly describe how mutation/disruption of neurofilaments in neurones may lead to neurodegeneration in ALS. (1)
Disorganised neurofilaments block axonal transport
Briefly describe 3 ways in which superoxide dismutase 1 mutations (gain of function mutations) may cause damage/death of motor neurones in ALS. (3)
- Mutated form doesn’t bind zinc properly so loses function (has to bind copper and zinc to work)
- Mutated form can aggregate
- Aggregates bind peripherin (type of intermediate filament) to form spheroids and interrupt neurofilaments
Transgenic mouse studies have been used to investigate the causes of ALS/MND.
Describe what you would expect to see if mice had increased peripherin or SOD1. (1)
Both cause MND symptoms
Describe how mouse KO of EAAT2 may provide evidence for the aetiology of ALS. (3)
EAAT2 KO show reduced glial glutamate transport (in astrocytes)
So increased glutamate in synapse
Which may cause excitotoxicity in ALS
Describe a disease-modifying treatment currently used for ALS. (1)
There are none - can only try to treat symptoms
Give three possible supportive treatments for respiratory issues in ALS. (3)
- Airway clearance
- Ventilation
- Respiratory strength training
How is pain generally treated in ALS? (1)
Give an issue with treating pain in ALS. (1)
Standard analgesics, particularly opiates
An issue is that opiates can contribute to respiratory depression
Give a drug (and its class) that can be used to treat spasticity in ALS. (1)
Baclofen (GABA-B agonist)
Give three potential treatments which may help to slow progression of ALS. (3)
Riluzole
Sodium Phenylbutyrate and Taurursodiol
Edaravone
How might riluzole slow down progression of pathology and symptoms in ALS? (1)
Decreases glutamatergic neurotransmission
How is sodium phenylbutyrate and taurursodiol proposed to slow progression of ALS? (2)
- Reduces ER stress
- Reduces mitochondrial dysfunction
How might edaravone slow disease progression in ALS? (1)
Scavenges free radicals
Why is edaravone approved for treating ALS in the US but not Europe? (1)
Lack of efficacy
Given that decreased spinal AChRs and ChAT are seen in ALS, suggest a possible treatment. (1)
Why isn’t this treatment currently used? (1)
Lecithin (ACh precursor)
Showed no benefit to patients
Given that increased incidence of ALS is observed after infection with the polio virus, suggest a possible treatment? (1)
Why isn’t this treatment currently used? (1)
Amantadine (antiviral drug)
Showed no benefit to patients
Given that increased plasma IgG levels are observed in patients with ALS, suggest a possible treatment. (1)
Why isn’t this treatment currently used? (1)
Plasmapheresis with cyclosporin (T-cell suppression)
Showed no benefit to patients
Given that decreased thyrotropin releasing hormone is seen in the CSF and spinal motor neurones of patients with ALS, suggest a possible treatment. (1)
What are the effects of this treatment in patients? (2)
How might this treatment work? (1)
TRH analogues
EFFECTS:
- transient strength increase
- Disease progression unaltered
TRH and its analogues excite motor neurones
Given that a growth factor deficiency is seen in motor neurones in ALS, suggest a possible treatment. (1)
Why is this treatment not currently used. (1)
BDNF
It was toxic in clinical trials
Give two potential disease modifying treatments for ALS which are being developed. (2)
- Gene therapy
- Stem cells
Describe a specific gene therapy that is currently being developed for ALS. (2)
Anti-sense oligonucleotide for downregulation of SOD1
Drug is called Tofersen
How to antisense oligonucleotides work? (2)
Bind to specific mRNAs
and reduce or alter their translation into proteins.
Describe an issue with using antisense oligonucleotides against SOD1 (Tofersen) to treat ALS. (1)
Will only work for patients with SOD1 mutation (about 2% of patients)
Why is it thought that antisense oligonucleotide therapy against C9orf72 gene/protein has not been successful in treating ALS? (1)
We don’t have precise knowledge of the gene function
How might stem cells (eg. adult bone marrow mesenchymal stem cells) be used to treat ALS? (1)
Can differentiate into astrocytes and microglia and perform neurotrophic functions
(cannot replace lost motor neurones)
What is the current clinical standing on using adult multi-potent stem cells to treat ALS? (3)
Effective in animal models
Some small clinical trials being conducted
Appears safe, but limited benefits reported
How are iPSCs from ALS patients currently used? (1)
How might this change in the future? (1)
Currently used to model disease
may be possible to use therapeutically in future
Which muscles does myaesthenia gravis typically affect? (1)
Typically affects muscles of the eye, but can affect any skeletal muscle.
Describe the main symptom seen in myaesthenia gravis. (2)
Muscle weakness
which is fatigable (worsens with use)
Is myaesthenia gravis more prevalent in men or women? (1)
What age does it typically present in each sex? (2)
More prevalent in women
Presents <40 in women
Presents >60 in men
Describe the pathology/aetiology of myaesthenia gravis. (1)
Autoimmune antibodies against nAChR or MuSK proteins at NMJ
In myaesthenia gravis, antibodies may be produced against MuSK.
What is MuSK? (1)
What is its normal role? (1)
Muscle-specific receptor tyrosine kinase
Involved in NMJ development
How is sensation affected in myaesthenia gravis? (1)
It is not
Which cells are responsible for producing the autoimmune antibodies seen in myaesthenia gravis? (1)
B cells
Give two functional changes seen at the NMJ in myaesthenia gravis. (2)
- Less muscle fibre depolarisation (less post-synaptic depolarisation; end plate potential reduced)
- Reduction in storage of ACh in vesicles
How could you use electrophysiology to show reduced vesicular storage of ACh in myaesthenia gravis? (1)
Measure miniature end plate potential - it will be reduced
(MEPP represents quantal release of one vesicle of ACh)
Describe how ACh release from motor neurones may be affected in myaesthenia gravis. (1)
MG might prevent release or cause less release
Give two structural changes (which could potentially be seen with a microscope) at the NMJ which occur in myaesthenia gravis. (2)
- Degradation of junctional folds
- Disruption of nicotinic receptors
Describe how edrophonium may be useful in helping to diagnose myaesthenia gravis. (3)
Edrophonium is a reversible and short-acting AChE inhibitor
Normal patients show little effect, but temporary dramatic improvement in muscle strength in MG patients
Can help differentiate between MG and ALS and Lambert-Eaton myaesthenic syndrome
Compare Myaesthenia gravis and Lambert-Eaton myaesthenic syndrome, in terms of symptoms and neurobiology. (2)
Same symptoms
NEUROBIOLOGY:
MG = Abs against NMJ proteins
LEMS = inability to produce ACh
Suggest five approaches to treating myaesthenia gravis. (5)
- Acetylcholinesterase inhibitors (AChE-Is)
- Immunosuppressants
- Plasmapheresis
- Removal of thymus gland
- Monoclonal antibody treatments
Give an example of an acetylcholinesterase inhibitor used to treat myaesthenia gravis. (1)
Describe how this may improve symptoms. (1)
Neostigmine
Slows the breakdown of ACh so more to bind to remaining receptors
Give two immunosuppressants which could be used to treat myaesthenia gravis. (2)
How might they improve symptoms? (1)
Corticosterone
Prednisone
Improve symptoms by suppressing antibody production
How might plasmapheresis work to improve symptoms and treat myaesthenia gravis? (1)
Removes antibodies from the circulation
How might removing the thymus gland help to treat myaesthenia gravis? (1)
Rebalances the immune system
How might monoclonal antibody treatments help to treat myaesthenia gravis? (1)
Antibodies target immune cells to reduce production of autoantibodies.
