Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Neuroanatomy and neurodegenerative disorders > Amyotrophic Lateral Sclerosis > Flashcards

Amyotrophic Lateral Sclerosis Flashcards

1
Q

What is amyotrophic lateral sclerosis (ALS)?

A
  • A rapidly progressive and fatal neurodegenerative disease characterised by gradual degeneration and death of motor neurons
  • Most common type of motor neuron disease
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Who tends to develop ALS?

A
  • People aged 40-70 years old
  • Average age of onset is 55
  • ALS occurs throughout the world with no racial, ethnic or socioeconomic boundaries
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

How common is MND?

A
  • 5000 people in the UK and 300,000 worldwide live with MND
  • ALS is responsible for 2 deaths per 100,000 people per year
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the 3 types of ALS?

A
  • Sporadic - most common form of ALS
  • Familial - inherited disease (only accounts for 5-10% of cases)
  • Guamanian - extremely high incidence of ALS in Guam during the 1950s
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are some of the clinical symptoms of ALS at the onset of the disease?

A
  • Limbs - weakness of grip, decreased dexterity, foot drop, leg stiffness and tripping
  • Throat - slurred speech, difficulty chewing or swallowing
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are some of the clinical symptoms of ALS as the disease progresses?

A
  • Limbs - unable to hold objects, write, feed or use the toilet, unable to walk, stand or turn over in bed
  • Throat - unable to speak, swallow food or saliva
  • Breathing - breathless on exertion or lying flat
  • Cognition - dementia is rare but subtle deficits are common
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Death occurs at an average of 22 months after diagnosis. What is the most common reason for this?

A

Respiratory depression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are motor neurons?

A

Specialised nerve cells in the brain and spinal cord which transmit electrical signals to muscle for generation of movement

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Where are upper motor neurons located?

A

In the motor cortex and travel down the spinal cord to connect at different levels of cells known as lower motor neurons

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Where do lower motor neurons travel to?

A

Out of the spinal cord (i.e. along arms and legs) to connect to muscle

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the main consequence of motor neurons being damaged?

A

Difficulty with voluntary movement

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are some upper motor neuron symptoms seen in MND?

A

Modest weakness, stiffness, spasticity, hyper-reflexia, extensor plantar response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are some lower motor neuron symptoms seen in MND?

A

Major weakness, muscle wasting and fasciculations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How is MND diagnosed?

A
  • Neurophysiology - electromyography and nerve conduction studies
  • Neuroimaging
  • Blood tests
  • Diagnosis is based on the exclusion of other conditions that mimic MND and good clinical judgement
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

How long is a diagnosis generally made after symptom onset?

A

12 months

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is seen in both motor neurons and astrocytic in ALS?

A

Proteinaceous inclusions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is the basic pathology underlying ALS?

A

Degeneration of the upper and lower motor neurons in the motor cortex, brain stem and spinal cord

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Why do people with MND develop paralysis?

A
  • Pyramidal motor neurons in the frontal lobe degenerate and die causing severe spasticity and mild weakness of muscle groups
  • Motor neurons in the spinal cord degenerate and die causing wasting and major weakness of muscle groups
  • The degenerative process spreads until almost all MNs are affected, resulting in complete paralysis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What initiates the degeneration of motor neurons?

A

Mutant or damaged proteins accumulate inside motor neurons, initiating their degeneration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What proportion of genes for MND/ALS are known and can be offered for diagnostic and predictive testing in patients?

A

50% of familial and 5% of sporadic MND/ALS genes are known

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

How does gene testing help MND patients?

A

Excluding the presence of gene mutations can be greatly reassuring IVF and gene testing - defective genes can be prevented from recurring in future generations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Why do we focus on familial MND genes?

A

Only 1 in 10 people with MND have a family history of MND, almost everyone is fearful of passing it on to their children MND causing mutations can be used to model disease in cells and animals, allowing us to study disease mechanisms and develop therapies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Why do motor neurons degenerate?

A

Trans-activation response DNA-binding protein of 43 kDa (TDP-43) accumulates in the cell body of motor neurons in 95% of all MND cases causing formation of aggregates

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What do chick spinal neurons expressing TDP-43 mutant forms display?

A

Cytoplasmic aggregates, a reduction in the axonal length and cellular toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What does expression of high levels of TDP-43 protein cause on a Tunel stain and what does this indicate?

A

Increased staining which indicates apoptosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What causes 20% of familial cases of ALS?

A

Dominant mutations in the protein Cu/Zn superoxide dismutase (SOD1)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What does the A4V substitution of SOD1 cause in ALS?

A
  • This is the most common mutation in familial ALS
  • It results in an aggressive disease course with mean survival of 1 year after onset
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What does SOD1 do?

A
  • Converts superoxide radicals to hydrogen peroxide and oxygen
  • It is a metalloprotein and is a key enzyme involved in anti-oxidant defence mechanisms
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Where is SOD1 found within the cell?

A

In the cell cytosol, nucleus and mitochondrial membrane

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

How many SOD1 mutations have been found in ALS and what animal model has enhanced the understanding of the mechanisms underlying MN degeneration in ALS?

A
  • More than 140 mutations have been found
  • Transgenic rodents expressing different SOD1 mutations replicate the clinical and pathological features of ALS
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What is the role of mutated SOD1 in ALS?

A
  • Early studies of mutant SOD1 indicated that disease is not due to loss of enzyme activity
  • Mice engineered to completely lack SOD1 do not develop ALS
  • Mutations must cause SOD1 to gain a toxic property
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What are some potential cellular mechanisms underling ALS?

A

Oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, glutamate excitotoxicity, growth factor deficiency, glial cell pathology, Ca dysregulation, defective axonal transport

33
Q

Mutations in SOD1 cause structural changes in SOD1 that expose the Cu site to aberrant substrates. What do SOD1 mutations catalyse the Cu-mediated breakdown of ?

A

Hydrogen peroxide to hydroxyl radicals, causing oxidative damage

34
Q

What is another possible substrate that involves Cu-mediated oxidative damage?

A

Peroxynitrite causes nitration of tyrosine residues in target proteins to kill cells

35
Q

What are some examples of neurodegenerative disorders in which abnormal protein aggregation is a common feature?

A

AD, PD, HD

36
Q

Where can abnormal protein aggregation be found in patients with HD?

A

Intracellular cytoplasmic inclusions are evident in MNs and glial cells in mouse ALS models and in human ALS

37
Q

What substance can be found in protein aggregates of HD patients?

A

Misfolded SOD1 - mutated SOD1 has an increased propensity for aggregation

38
Q

Why are protein aggregates toxic?

A
  • Loss of protein function through co-aggregation
  • Depletion of chaperones such as Hsp-70
  • Clogging of proteasome with misfolded proteins
  • Dysfunction of mitochondria and/or other organelles
39
Q

Is there a role for mitochondria in ALS and if so what is it?

A

Yes histological studies have shown mitochondrial abnormalities at early stages of ALS and in mouse ALS models

40
Q

What kind of mitochondrial abnormalities have been found in sporadic ALS?

A

Impairments in electron transport chain function have been found

41
Q

What does mutant SOD1 do to mitochondrial function?

A
  • Directly disrupts mitochondrial function
  • Aggregates of mutant SOD1 are found within mitochondria
  • Mutant SOD1 disrupts cytochrome C association with inner mitochondrial membrane which interferes with respiration
42
Q

What is an important consequence of disturbed mitochondrial function?

A

The production of reactive oxygen species (ROS)

43
Q

What happens to glutamate in ALS?

A
  • In MNs, glutamate is cleared from synapses by the glial glutamate transporter, EAAT2
  • In sporadic ALS, glutamate levels are elevated in the CSF, suggesting abnormal glutamate handling
  • In ALS, glutamate transport is markedly reduced in affected brain regions due to pronounced loss of EAAT2
44
Q

What would lowering EAAT2 levels do to motor neurons?

A

It would induce neuronal death as there would be loss of glutamate transport activity

45
Q

What does mutant SOD1 do to EAAT2 levels?

A
  • In mutant SOD1 transgenic strains, EAAT2 protein levels are markedly reduced
  • Mutant SOD1 selectively inactivates the glial glutamate transporter EAAT2
46
Q

What is the role of vascular endothelial growth factor in ALS?

A
  • Targeted deletion of part of VEGF gene causes motor deficits and ALS pathology, suggesting putative role for VEGF in ALS
  • Onset and progression of ALS is delayed in mutant SOD1 mice if there is; overexpression of VEGF, ICV administration of VEGF or IM delivery of VEGF-expressing lentiviral vectors
47
Q

Other than VEGF, what other growth factors can delay disease onset and progression in mutant SOD1 mice?

A

IGF-1 and GDNF

48
Q

What is the role of glial cells in ALS?

A
  • Growing evidence that glial cells contribute to disease progression
  • Astrocytic inclusions are an early indicator of SOD1 mutant toxicity
49
Q

Why are astrocytes expressing mutant SOD1 toxic to motor neurons?

A

They secrete factors that are toxic to MNs potential secreted agents are: proinflammatory cytokines and chemokines

50
Q

What is the role of neurofilaments in ALS?

A
  • Neurofilaments are the most common cytoskeletal protein in MNs and play a key role in axonal growth
  • Abnormal accumulation of neurofilaments in soma and axons of MNs is a hallmark of ALS
51
Q

What evidence is there in mice for the role of neurofilaments in ALS?

A
  • Transgenic mice with mutations or overexpression of neurofilaments display MN dysfunction
  • Mutant SOD1 mice have defective axonal transport
52
Q

Why is there selective degeneration of motor neurons in ALS?

A
  • Only motor neurons degenerate in familial ALS despite expression of mutant SOD1 in every cell
  • One possibility is that MNs are more susceptible to excitotoxicity
53
Q

What properties of spinal motor neurons are crucial for normal function but under pathological conditions could promote MN death?

A
  1. Receive very strong glutamatergic inputs
  2. Express Ca permeable AMPA receptors
  3. Have low Ca buffering capacity
54
Q

What makes motor neurons very vulnerable to excitotoxicity?

A

They have much lower Ca buffering capacity than other neurons and they express a high number of Ca permeable AMPA receptors

55
Q

Under normal conditions, how is Ca regulated in motor neurons?

A
  • Glutamate stimulates Ca permeable AMPARs which increases intracellular Ca
  • Due to low Ca buffering, some of the Ca is taken up by mitochondria
  • Astrocytic glutamate transporter removes glutamate from synapses
  • Factors released from astrocytes increase GluR2 expression in nearby MNs
56
Q

What does the presence of mutant SOD1 in MNs do to Ca regulation?

A
  • The presence of mutant SOD1 in neurons and astrocytes interferes with the process of Ca regulation
  • The balance is shifted from normal glutamatergic communication between neurons to excitotoxic MN death
57
Q

What is the role of GluR2 in ALS?

A
  • Lack of GluR2 accelerates MN degeneration and shortens life span in mutant SOD1 mice
  • Replacement of GluR2 in mutant SOD1 mice significantly increased life span
58
Q

What are the potential effects of a SOD1 mutation in ALS?

A
  • Can cause dysfunction of glial cells and disrupt normal synaptic communication
  • Can also cause excitotoxic cell damage due to effects on mitochondria
  • Marked downregulation of expression of EAAT2
59
Q

What are the key pathological features of ALS?

A
  • SOD1 mutation and loss of glial glutamate transporter
  • These suggest excess extracellular glutamate triggers harmful Ca influx leading to downstream neurotoxicity (loss of mitochondrial function and oxidative stress)
60
Q

What was the mechanism of action of some of the first therapies tested in ALS rodent models?

A

Agents that block glutamate excitotoxicity e.g. antioxidants and/or glutamate receptor antagonists

61
Q

What is riluzole and how effective is it?

A
  • The only approved drug to treat ALS
  • Extends survival by 2-3 months but does not confer any long-lasting protection
62
Q

What are some of the acute effects of riluzole in animal models and what do these effects all act to do?

A
  • Decreasing persistent voltage-gated Na currents, potentiation of a Ca-dependent K current and inhibiting glutamate release
  • These effects all act to decrease MN excitability
  • Thus riluzole may act by limiting excitotoxicity
63
Q

Name some examples of novel therapeutic targets in ALS?

A

Presynaptic neuron, mitochondria, mutant SOD1 mRNA, neuronal cytoplasmic inclusions, muscle, EAAT2 astrocyte glutamate transporter

64
Q

How is ceftriaxone proposed to treat ALS?

A
  • Ceftriaxone is an antibiotic
  • It increases glial mediated glutamate transport by stimulating expression of EAAT2
  • In animal models of ALS, it prolongs survival and upregulates EAAT2 mRNA
65
Q

What is the role of heat shock proteins (HSP) in ALS?

A
  • HSPs are involved in protein folding and degradation
  • Abnormalities in HSPs promote MN degeneration in ALS
66
Q

How is arimoclomol proposed to treat ALS?

A
  • Arimoclomol is an oral agent that increases expression of HSPs involved in neuroprotective mechanisms
  • It delays disease progression and extends life span in SOD1 transgenic ALSL models
67
Q

What does mutant SOD1 do to mitochondrial function?

A

It interferes with normal mitochondrial function and can lead to apoptosis through disruption of mitochondrial respiration

68
Q

What are some examples of ALS drugs that target mitochondria?

A
  • Olesoxime - mitochondrial pore modulator - delays disease onset and extends survival in SOD1 mutant mice
  • Dexpramipexole - lowers oxidative stress and maintains mitochondrial function - extends survival of SOD1 transgenic mice
69
Q

How is stem cell therapy proposed to treat ALS?

A
  • Stem cells would be directed to the damaged area and provide necessary growth factors to the dying motor neurons and other cells
  • Embryonic stem cells can generate motor neurons in the lab
70
Q

What is necessary for stem cell therapy to be effective in ALS?

A
  • Stem cells must differentiate into MNs and replace dead MNs and also make connections to denervated muscle
  • Motor neurons must connect to muscle fibres over distances of up to 3 metres. Making this connection is vital to regeneration of activity
  • An additional concern is immuno-rejection by the body’s own immune system
71
Q

What recent advances have been made in stem cell therapy in ALS rats?

A
  • Cells are modified to deliver specific genes to regenerate damaged MNs (GDNF)
  • Cells that thrived in rat models involved 2 points of injection (MNs and affected muscle)
  • These rats displayed slower disease progression and increased survival rate
  • These results were due to increased production of nerve projections from MNs in spinal cord to the muscles
72
Q

Respiratory failure is the main cause of death in ALS. What muscle target would be extremely beneficial in ALS treatment?

A
  • Improving diaphragm function can improve QOL and survival
  • Agents that strengthen diaphragm/muscle function may have clinical benefit
73
Q

What drug has been shown to increase muscle mass and volume and could therefore be used in ALS?

A
  • ACE-031 is a protein that inhibits negative regulators of muscle growth
  • Subcutaneous treatment with ACE-031 is well tolerated in humans and it increases muscle mass and volume
74
Q

What is a drug that increases muscle force and could thus be used in treating ALS?

A
  • CK-2017357 activates fast skeletal muscle troponin complex by increasing sensitivity to Ca. This increases muscle force.
  • Treatment is well-tolerated and muscle strength and pulmonary function improve compared to placebo
75
Q

What can be used to lower mutant mRNA such as mutant SOD1 and what impact does this have on disease progression?

A
  • Antisense oligonucleotides and small inhibitory RNAs can lower mutant mRNA
  • This approach slows disease progress and increases survival in SOD1 transgenic mice
76
Q

How is VEGF produced in health?

A

mRNA stabiliser HuR binds to VEGF mRNA, resulting in sufficient VEGF protein for neuroprotection and oxygen supply to motor neurons

77
Q

What happens to VEGF in ALS?

A

Mutant SOD1 competes with HuR for binding, reducing VEGF and compromising neuroprotection and perfusion, leading to MN degeneration

78
Q

How would VEGF therapy work in ALS?

A
  • Recombinant VEGF is delivered intracerebroventricularly to provide degenerating MNs an increased neuroprotective survival signal and improved oxygen supply
  • Could restore neuroprotection to neurons and increase potential to regenerate connections to muscles

Neuroanatomy and neurodegenerative disorders (7 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions