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Molecular Basis Of Disease > Amyotrophic Lateral Sclerosis > Flashcards

Amyotrophic Lateral Sclerosis Flashcards

1
Q

What is ALS also known as

A

Chercot’s disease
Lou Gehrig’s disease

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2
Q

What is ALS

A

a neurodegenerative disorder which causes muscle wasting (amyotrophy) which impacts physical function

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3
Q

loss of what cases ALS?

A

loss upper motor neurons:
- cortical
- brain stem
- spinal motor neurons

loss of lower motor neurons:
- bulbar
- spinal motor neurons

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4
Q

What is lateral sclerosis?

A

hardening of lateral corticospinal column (side of spine where brain tells muscle what to do)
- forms scleortic plaques (scarring lesions) similar to MS

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5
Q

When is onset of ALS?

A

adult onset
- after 20 usually at 50-60

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6
Q

Why does Guam have high ALS and Parkinson’s like disease complex?

A

cycad toxicity
- bats eat specific plant found in this area and accumulates toxicity over time
- human then eat the bats

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7
Q

Which sex is more affected by ALS?

A

males

MS is higher in females

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8
Q

what is the average survival once diagnosed with ALS?

A

about 3-5 years
- 50% die within 30 months of symptom onset
- 20% survive between 3-5 years after onset

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9
Q

What is death usually caused by in ALS patients?

A

breathing stops due to loss of brainstem motor neurons (medulla/bulb area of brainstem)

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10
Q

What are some other ways ALS patients die?

A

pneumonia
- swallowing difficulties cause food, liquids, saliva in lungs
malnutrition and dehydration
- dysphagia (difficulty swallowing) due to brain stem defects
heart problems
- arrhythmia or irregular heart beats

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11
Q

What are general features of ALS?

A

weakening due to:
- atrophy (loss of muscle mass)
- amyotrophy (progressive wasting of muscle)
hyperreflexia (overactive reflexes)
fasciculation (involuntary muscle contractions/twitches)
spasticity (certain muscles continuously contracted - claw hand)

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12
Q

Each whole muscle is innervated by a number of different motor neurons from the spinal cord. Why does this cause implications?

A

each muscle fibre is innervated by only ONE motor neuron which innervates multiple muscle fibres
therefore a loss of one neuron leads to numerous muscle fibre loss

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13
Q

Where do corticospinal motor neurons (upper motor neurons) originate from?

A

cortex of the brain

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14
Q

Where do bulbar and spinal motor neurons (lower motor neurons) which innervate skeletal muscle originate from?

A

medulla/ spinal cord

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15
Q

What are the 4 main presentations of ALS

A
  1. limb onset
  2. bulbar onset
  3. primary lateral sclerosis
  4. progressive muscular atrophy
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16
Q

what is limb onset ALS?

A

combination of upper and lower motor neuron signs in limbs
- about 70% of cases

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17
Q

What is bulbar onset ALS?

A

speech and swallowing difficulties with limb features developing later
- 25% of cases

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18
Q

What is primary lateral sclerosis ALS?

A

only upper motor neuron involvement
- less common

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19
Q

What is progressive muscular atrophy ALS?

A

only lower motor involvement

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20
Q

There are 6 stages of progression for ALS. What is stage 1?

A
  1. mild focal weakness (single defect) with asymmetrical distribution (one side of body)
  2. hand cramping and fasciculation (all lower motor neurons)
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21
Q

There are 6 stages of progression for ALS. What is stage 2?

A
  1. moderate weakness in muscle groups
  2. some muscle atrophy present
  3. modified independence with assistive devices (e.g. walkers)
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22
Q

There are 6 stages of progression for ALS. What is stage 3?

A
  1. severe weakness of specific muscles
  2. increasing fatigue
  3. mild to moderate functional limitations related to walking
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23
Q

There are 6 stages of progression for ALS. What is stage 4?

A
  1. several weakness and wasting of muscle groups
  2. mild weakness of upper oesophagus (need moderate assistance)
  3. assistive devices required (wheelchair)
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24
Q

There are 6 stages of progression for ALS. What is stage 5?

A
  1. progressive weakness with deterotiation of mobility and endurance
  2. moderate to severe muscle weakness (whole limbs/trunk)
  3. spasticity
  4. hyperreflexia (upper motor neurons)
  5. loss of head control
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25
Q

There are 6 stages of progression for ALS. What is stage 6?

A
  1. bedridden
  2. need a full time carer
  3. progressive respiratory distress
26
Q

What is the cause of ALS symptoms?

A

upper and lower motor neurons generate or die losing the communication to muscle
- promotes progressive muscle weakening and muscle of fasciculation

27
Q

What is fasciculation?

A

brief spontaneous contraction affecting a small number of muscle fibres in a muscle group

this causes a flicker of movement under the skin

28
Q

What is glutamate excitotoxicity?

A
  1. glutamate is released by pre-syn neuron to act on post-syn neuron
  2. excess glutamate in the synapse is taken up by astrocytes through glutamate transporters
    - mutant SOD1 leads to lack of glutamate uptake in astrocytes
  3. excitotoxicity of postsynaptic neuron as glutamate keeps innervating post-syn
29
Q

Glutamate excitotoxicity leads to an increase in what other substance in the post-syn neuron?

A

Ca2+ as glutamate triggers uptake

30
Q

What does excess Ca2+ in neurons cause?

A

activation of:
- phospholipases
- endonucleases
- proteases

causes changes to:
- membranes
- DNA
- proteins
in post syn neuron which can lead to death

31
Q

What is the hallmark present in motor neuron cytoplasm in ALS?

A

inclusion bodies (abnormal aggregation of proteins

32
Q

What theoretical changes cause neuronal degeneration in ALS?

A

glutamate excitotoxicity

generation of free radicals

cytoplasmic protein aggregation (SOD1 and other proteins)

mito dysfunction

neurofilament intracellular aggregates disrupts axonal transport

activation of microglia secretes proinflam cytokines and further toxicity

ultimately motor neuron generation occurs through activation of calcium-dependant enzymatic pathways

33
Q

ALS gene mutations are mostly sporadic. Why is there little success in identifying susceptibility genes?

A

complex genetic basis

34
Q

2 major genes have been associated with ALS. They are C9ORF72 and SOD1. What changes in a mutated C9ORF72 protein and how is it related to ALS?

A

change = polymorphic hexanucleotide (GGGGCC) repeat

found in 30-50% FALS
5-7% of SALS

35
Q

2 major genes have been associated with ALS. They are C9ORF72 and SOD1. What are the phenotypic changes caused by SOD1 mutation?

A

limb onset starting predominantly in lower limbs

shorter survival with death occurring in less than 1.5 years

36
Q

2 major genes have been associated with ALS. They are C9ORF72 and SOD1. What is the difference in FALS and SALS associated to mutant SOD1?

A

SALS = 1%
FALS = 13%

37
Q

TARDBP/TPD43 is another major ALS causing gene. What protein is the product of this gene?

A

TAR DNA binding protein

38
Q

TARDBP/TPD43 is another major ALS causing gene. How is the product of this gene involved in ALS pathophysiology?

A

main component of inclusion bodies in 97% of ALS cases

39
Q

TARDBP/TPD43 is another major ALS causing gene. What is the percentages of this protein associated with FASL and SALS cases?

A

FALS = 3%
SALS = 1.5%

40
Q

FUS is another major ALS causing gene. What is this genes name and what is its association with FALS and SALS cases?

A

fused in sarcoma

FALS= 5%
SALS = 1%

41
Q

What is C9orf72 known as?
High repeats when mutated causes what change in this protein expression?

A

chromosome 9 open reading frame 72

high repeats cause down regulation of gene expression

42
Q

Where is C9orf72 protein located in neurons and how could this be linked to ALS?

A

at pre-synaptic membrane
- important for sending and receiving signals between neurons

thought to play a role in glutamate handling

43
Q

What is the function of C9orf72 normally?

A

involved in transcription, translation and transport of RNA in a cell

44
Q

The GGGGCC repeat expansions in C9orf72 gene is located between exon 1a and 1b. This leads to 3 different pathogenic outcomes. What is the consequence of no transcription occurring of exon 1b?

A

disrupts transcription of wild type C9orf72 allele

45
Q

The GGGGCC repeat expansions in C9orf72 gene is located between exon 1a and 1b. This leads to 3 different pathogenic outcomes. When transcription does occur of the antisense strand 2 complementary RNA transcripts are produced which can form a loop. What are the 2 consequences of this?

A
  1. triggers RNA mediated toxicity which disturbs the normal function of RNA binding proteins
  2. causes dipeptide repeat protein toxicity causing protein aggregation
46
Q

Where is SOD found and what is its structure?

A

cytoplasm

homodimer with 1 zinc and 1 copper atom
- copper is related to activity of SOD
- zinc is for structure

47
Q

What is the function of SOD

A

detoxifies superoxide radicals to hydrogen peroxide and oxygen

48
Q

Mutant SOD1 leads to a toxic gain in function. What does mutant SOD1 lead to?

A
  1. unchecked generation of free radicals
    - mtDNA oxidative damage
  2. confirmation instability of SOD1 peptide
    - intracellular aggregates
    - inhibits normal proteosomic function
    - disrupts axonal transport systems and cellular functions
  3. impaired glutamate uptake in astrocytes
49
Q

Mutant SOD1 forms 3 altered SOD1 structures: Cu+Zn dimer, Cu+Zn monomer and Zn deficient dimer. What happens when Cu+Zn dimer is formed?

A

the improper formations causes binding to other proteins and aggregates
- loss of function due to aggregation

50
Q

Mutant SOD1 forms 3 altered SOD1 structures: Cu+Zn dimer, Cu+Zn monomer and Zn deficient dimer. What occurs when a Cu+Zn monomer is formed?

A

only 1 monomer = not active so binds to HSP70 and other chaperones to protect hydrophobic regions
- causes aggregates

51
Q

Mutant SOD1 forms 3 altered SOD1 structures: Cu+Zn dimer, Cu+Zn monomer and Zn deficient dimer. What happens when Zn-deficient dimer is formed?

A

causes aggregates and reduces proteasome activity as it is busy degrading this mutant

52
Q

On histology findings of sporadic ALS what is seen?

A

age related post translational modification of SOD

53
Q

On histology findings of familial ALS what is seen?

A
  • cytochemical evidence of excitotoxcity
  • abnormalilities of glutamate metabolism
54
Q

What factors contribute to the death of motor neurons in ALS?

A
  • accumulation of superoxide radicals and oxidative stress (SOD1 mutations)
  • altered protein homeostasis leading to aggregation
  • abnormal RNA processing
  • neuronal cytoskeleton disruption (neuronal filament aggregates)
55
Q

There are 3 hypothesis exploring where ALS begins. What is the dying forward hypothesis?

A

begins centrally with corticomotor neuronal hyperexcitability causing anterior horn cell degeneration (through glutamate excitotoxicity)

anterior horn = neuronal cell bodies in corticospinal tract

56
Q

There are 3 hypothesis exploring where ALS begins. What is the dying back hypothesis?

A

begins in lower motor neurons (at muscle cells/neuromuscular junction)

57
Q

There are 3 hypothesis exploring where ALS begins. What is the independent degradation?

A

simultaneously occur in upper and lower motor neurons

58
Q

How is MRI used as a detection method for ALS?

A

MRI corticospinal tract hyperintensity (high bright signal in corticospinal tract)

59
Q

How is PET scanning used as a detection method for ALS?

A

uses PK11195 as a radiotracer
- this assesses levels of translocator protein which is a marker for inflammation

60
Q

How is electromyogram (EMG) used as a detection method for ALS?

A

fine needles are placed into selected muscles which records resting and voluntary contraction electrical activity

61
Q

There is no cure for ALS but the drug riluzole can be used. How does Riluzole work?

A

inhibits glutamate release from neurons but the mechanisms are not understood

can prolong survival for 2-3 months

Molecular Basis Of Disease (17 decks)

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