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Neuroscience and Mental Health > Motor Neuron Disease/Amyotrophic Lateral Sclerosis (ALS) PART I > Flashcards

Motor Neuron Disease/Amyotrophic Lateral Sclerosis (ALS) PART I Flashcards

1
Q

Define Motor Neuron Disease/ Amyotrophic Lateral Sclerosis (ALS)

A

Chronic neurodegenerative condition causing
muscle wasting, paralysis and death usually
within 3-5 years due to respiratory failure

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2
Q

Neuropathological features of ALS?

A
  • Amyotrophy

- scarring of the corticospinal tracts

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3
Q

Compare ALS risk in men vs women

A

Greater in men

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4
Q

Specific targets of ALS?

A

Upper motor neurons and Lower motor neurons

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5
Q

What makes UMN and LMN vulnerable to ALS severe symptoms?

A 
- Both have long axons
(length / cell diameter
~10,000)
- Very active
- High energy demands
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6
Q

Briefly describe the outcomes of UMN and LMN pathology in ALS

A

UMN -> spasticity

LMN -> atrophy

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7
Q

Describe the features of ALS symptoms

A
  • progressive denervation + secondary muscle weakness of limbs, trunk, tongue, resp (intercostal) muscles
  • Impaired speech & swallowing (bulbar signs)
  • Spastic weakness + paralysis in almost all skeletal muscle
  • NO impairment of bladder/bowel/sexual function
  • SPARED occulomotor/sensory/autonomic function

{NB: cognitive function affected in a minority of cases]

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8
Q

Describe the onset and progression of ALS

A

Starts focally and spreads

Usually starts in distal muscles of limb/bulbar and then spreads

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9
Q

Specific examples of early ALS symptoms

A
  • Wasting of thenar eminenence

- Wasting of the tongue (bulbar)

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10
Q

Early diagnostic tests for ALS (and positive results)?

A
  • Muscle biopsy -(stain for ATPase)-> atrophic fibres

- Electromyogram (nerve conduction test) -> impaired conduction (and compensatory mechanism)

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11
Q

How do motor units compensate for the effects of ALS

A

Sprouting of neighbouring axons from neighbouring motor units (collateral branches)

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12
Q

How to distinguish ALS from other motor neurone diseases?

A

Presence of both upper and lower motor neurone signs

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13
Q

Examples of LMN signs?

A

Muscle weakness, wasting, fasciculations, cramps

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14
Q

Examples of UMN signs?

A

Stiffness, slowness of movement, slow and clumsy speech, Babinski

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15
Q

What could bulbar symptoms indicate in the context of ALS?

A

(i.e. UMN and LMN)

Progressive bulbar palsy

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16
Q

Describe Primary Lateral Sclerosis (PLS)

A

Effects on UMNs predominate:

  • spasticity
  • hyperreflexia

{20 yr survival)

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17
Q

Features of an MRI of pt with ALS (PLS)

A
  • Wide precentral sulcus

- Atrophy of adjacent gyri

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18
Q

Give an overview of the treatment of ALS

A

speech & swallowing- speech therapist

mobility around home- occupational therapist

swallowing & feeding- NG tube or PEG

breathing- oxygen, assisted ventilation

slowing disease progression- Riluzole (extends survival ~3 months_

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19
Q

Sites targeted in ALS?

A
  • motor cortex (UMN)
  • brainstem (LMN)
  • spinal cord (LMN)
20
Q

Histological features of ALS?

A

Ubiquinated inclusion in neuronal cell bodies and proximal axons

21
Q

What is an ubiquitinated protein?

A

Post-translational modification by a small 76 amino acid regulatory protein, ubiquitin

Substrate designated for degradation is tagged w/ ubiquitin. This is recognised by proteosome, which carries out this process.

22
Q

Ubiquitinated proteins are characteristic of what conditions?

A

ALS (sporadic & familial) and a subset of fronto-temporal dementia

23
Q

Two forms of ubiquitinated inclusions?

A
  • filamentous

- compact

24
Q

What protein is a major component of ubiquitinated inclusions (in SALS/FALS/FTLD)?

A

TDP-43

25
Q

What proportion of ALS cases are familial?

A

10%

26
Q

What is the molecular mechanisms that have been identified in ALS?

A

Abnormalities in:

  • RNA binding proteins
  • proteostasis

(- cytoskeletal proteins)

27
Q

Gene pathways involved in FALS?

A
  • RNA processing]- (TDP-43, FUS)
  • protein quality control (“waste disposal”)]- (VAPB, P4HB, SOD1, VCP, ubiquitin2, P62, OPTN
  • excitotoxicity]- DAO
28
Q

What gene encodes for TDP-43?

A

TARDBP (TAR DNA binding protein)

NB: TAR = Trans activating response

29
Q

Describe the actions of TARDBP

A

TARDBP encodes TDP-43

Binds TAR DNA sequences in DNA/RNA, acting as a transcriptional repressor

i.e. inhibits splicing and regulates mRNA transport/local translation

30
Q

Sites possibly responsible for TDP-43 and FUS mislocalisation?

A
  • Nuclear localisation signal (enable protein to be taken into nucleus)]- FUS
  • Nuclear export signal (enable protein to leave nucleus -> cytoplasm)]- (Importin is the nuclear transport protein)
31
Q

Difference in TDP-43 staining in healthy people and ALS patients

A

TDP-43 appears in cell nuclei in healthy people

TDP-43 is located in the cytoplasm in ALS patients

32
Q

Effect of TDP-43 mutation in animal models?

A

Neurodegeneration (cortical and spinal neurons) but not consistent forming of inclusions (present in both wild-type and mutant rodents)

33
Q

What genetic changes are found in FALS and FTLD?

A

FUS positive inclusions

34
Q

What is FUS/TLS?

A

FUS: fused in sarcoma

TLS: translocation in liposarcoma

35
Q

What process is TARDBP and FUS both involved in?

A

Regulation of RNA processing

36
Q

Effects of TDP-43 on transcription and mRNA splicing?

A

Transcriptional repressor

Exon skipping (binds to CFTR pre-mRNA UG intronic tract)

37
Q

Effects of FUS on transcription and mRNA splicing?

A

Transcriptional activator

Part of spliceosome machinery

38
Q

Main target of action for TDP-43 and FUS

A

Introns

39
Q

Describe the cytoplasmic stress granule response

A

Aims to conserves mRNAs during cell stress

Activity + cell stress stimulate nuclear efflux of TDP-43 and FUS to the cytoplasm, where they are withing RNA transport granules (stress granules and processing bodies)

40
Q

Effects of TDP-43 and FUS knockout on dendrites?

A

TDP-43 KO: reduced dendritic branching/ synapse formation

FUS KO: reduced spine formation

NB: TDP-43 regulates local protein synthesis on dendrites

41
Q

What causes TDP-43 mislocalisation?

A

Inhibition of TDP-43 nuclear transport protein (importin) -> accumulation of soluble TDP-43 in cytoplasm

NB: NLS is NOT affected in TDP-43

42
Q

What causes FUS mislocalisation?

A

mutation of nuclear localisation signal-NLS

[Experimental evidence]
Inhibition of FUS nuclear transport protein (transportin) -> FUS accumulation in cytoplasm

43
Q

Pathogenesis of SALS?

A

[nuclear transport proteins decrease w/ age -> increased cytoplasmic TDP-43]

  • cell stress/oxid. stress/heat shock/ER stress acts as the trigger
  • > stress granules in cytoplasm that contain housekeeping mRNAs that don’t require translation during stress also contain FUS and TDP-43

[NB: these stress granules could act as precursors for large inclusions]

44
Q

Relation of TDP-43 inclusions to ALS cases

A

Common to 97% of ALS cases (SALS and FALS)

Exceptions are FALS cases w/ FUS mutations (0.5% of ALS cases) and SOD1 (2% of ALS cases)

45
Q

Outcome of TDP-43 knock out in embryos?

A

Lethal

46
Q

Outcome of partial/conditional TDP-43 knockouts?

A

Motor neuron defects

Progressive motor phenotype

47
Q

Outcome of selective knockout of TDP-43 in glia/muscle

A

ALS-like phenotypes

Neuroscience and Mental Health (65 decks)

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