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BIOL354: Pathobiology > Lecture 4: Huntington's and Motor Neuron Disease > Flashcards

Lecture 4: Huntington's and Motor Neuron Disease Flashcards

1
Q

What are some of the clinical signs and symptoms of HD?

A

Involuntary bowing, twisting, grimacing movements often with facial and vocal tics

slow or abnormal eye movements

difficulty with speech and swallowing

sometimes memory problems/dementia

psychiatric symptoms (hallucinations and delusions)

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2
Q

What is usually the cause of death in HD?

A

patients often die 15-20 years after signs first appear from a secondary cause (such as heart failure)

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3
Q

Describe the pathology behind HD?

A

severe loss of neurons in the sub-cortical regions - largely in the caudate-putamen of the basal ganglia = brain weight reduced by about 30%

enlargement of lateral ventricles (CSF in lateral ventricles expands to fill the space and compensate due to loss of neurons)

Cells in cerebral cortex may also be affected (variable between people)

Gliosis (inflammation associated with neuronal death)

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4
Q

What are the alterations to neurotransmitter systems in HD (motor circuit)?

A

Glutamate excitotoxicity (primarily in the caudate putamen that drives the death of cholinergic and GABAergic neurons here)

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5
Q

How does dopamine neurotransmission differ in the early and later stages of HD?

A

biphasic changes in dopamine neurotransmission:
- early stages = increased dopamine release = contributes to hyperactivation of thalamus = increased stimulation of motor cortex that increases movement
- later stages = lose dopaminergic input

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6
Q

How does the biphasic changes in dopamine neurotransmission in HD affect response to treatments?

A

giving L-dopa (used to compensate for loss of dopamine) in early stages will aggravate symptoms but dopamine antagonists will alleviate symptoms

as the disease progresses, you might see a reversal of this

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7
Q

How is HD inherited?

A

autosomal dominant inheritance

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8
Q

What is the age of onset?

A

usually 40-50 (although children constitute about 10% of the cases)

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9
Q

What phenomenon is displayed by HD?

A

genetic anticipation (worsening of the disease phenotype over generations)

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10
Q

True or false: inheritance from mother is likely to result in more severe disease?

A

False: inheritance from father is likely to result in more severe disease

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11
Q

How does the number of CAG repeats relate to age of onset?

A

Individuals with higher number of CAG repeats have an earlier onset of disease

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12
Q

What is the name of the gene and protein involved in HD?

A

gene: IT-15

protein: huntingtin (Htt)

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13
Q

Where is huntingtin found?

A

throughout brain and in the testes

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14
Q

What is the function of huntingtin?

A

unknown but may act as a transcription factor or contribute to protein trafficking or endocytosis/membrane cycling in neurons

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15
Q

What evidence shows huntingtin is essential for normal embryonic development?

A

Huntingtin KO mice is embryonic lethal

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16
Q

True or false: HD is a repeat expansion disorder?

A

True

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17
Q

What is the nucleotide repeat implicated in HD?

A

trinucleotide CAG repeat within exon 1 of coding region of huntingtin near N-terminus

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18
Q

What three things does the length of the CAG repeat determine in HD?

A

Whether an individual will develop HD (E.g. 36 repeats and above = affected, 40 repeats and above results in adult-juvenile onset)
degree of penetrance
age of onset
disease severity

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19
Q

Describe the Huntingtin protein (Htt)

A

cytosolic protein with molecular weight around 350 KDa
- N-terminal PolyQ region begins at amino acid 18
- PolyQ region followed by PolyP (polyproline) region which is thought to keep the Htt in solution
- multiple HEAT domains that are thought to play a role in vesicle trafficking
- Nuclear export signal
- nuclear localisation signal

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20
Q

How is the wildtype huntingtin protein post-translationally modified to form non-toxic fragments?

A

don’t have the long polyQ repeat = cleavage of n-terminal fragment by caspases
- N-terminal fragment interacts with C-terminal fragment

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21
Q

How is the mutant huntingtin protein post-translationally modified to form toxic fragments?

A
  • long polyQ repeat domain = alternate cleavage of Htt to generate a larger N-terminal fragment that is not able to interact with the C-terminus (mis-folded) resulting in an aggregate property.
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22
Q

How do expanded polyQ Htt proteins aggregate?

A

form detergent-insoluble protein aggregates with characteristics of amyloid fibrils

  • aggregate into oligomers, intermediates then fibrils but still debate over which species is most toxic
23
Q

How does the distribution of Htt change in HD?

A

changes from cytoplasm to peri/nuclear (forms nuclear inclusions)

24
Q

Which neurons predominantly contain the Htt nuclear inclusions?

A

Neurons of the caudate-putamen and cortex

25
Q

What experimental evidence has suggested that Htt amyloid fibrils may be the more toxic species?

A

> 30 CAG repeats results in fibril formation with longer repeats aggregating faster and at lower concentrations

Htt inclusions form before the onset of neurological symptoms and neurodegeneration

so questions whether these aggregates are the cause of the disease

26
Q

What experimental evidence has suggested that Htt amyloid fibrils may be the least toxic species?

A

cultured human neurons and developed a robotic microscope that could track the fate of each cell in the dish
- expressed the GFP tagged Htt protein to see where the Htt distributed
- found that in some cells, they developed red Htt inclusions but the neuron was healthier than the neurons surrounding it

suggested that the neurons with intranuclear inclusions were actually protected from death and suggesting that perhaps the fibrillar species was actually the least toxic

27
Q

What are the potential targets of disease-modifying treatments for HD?

A
  • depletion or stabilisation of dopamine, serotonin and other monoamines involved in pathogenesis and biphasic responses
  • antioxidants to reduce free-radicals
  • anti-sense oligonucleotide treatment to silence the expression of the IT-15 gene (risky bc don’t understand the physiological role of the protein so maybe just target repeat domains in exon 1)
  • stem cell therapy
28
Q

What are some of the current treatments for HD?

A

Symptomatic treatments:
- physical therapy to treat motor issues
- rebalance the neurotransmitter systems (GABA, glutamate, acetylcholine, dopamine)

29
Q

What is motor neuron disease also called?

A

Amyotrophic lateral sclerosis

30
Q

What is MND?

A

progressive, fatal disease that attacks nerve cells controlling voluntary muscles

31
Q

What are some of the clinical features and symptoms of MND?

A

muscle atrophy, weakness and
muscle twitch that signify disease of the lower motor neurons

glial scar in the lateral columns of the spinal cord at autopsy following degeneration of the corticospinal tracts

loss of brain’s ability to initiate and control voluntary movement

difficulty speaking, swallowing and eventually breathing

32
Q

What is the typical cause of death in patients with MND?

A

respiratory failure

33
Q

True or false: dementia is often seen in individuals with MND nearer the end of disease?

A

False:
cognitive function is often spared but about 10% of cases develop a type of dementia

34
Q

What is the difference between upper and lower motor neurons?

A

Upper motor neurons originate in the motor cortex in the cerebral cortex and travel down to, and synapse in, the brain stem and spinal cord

lower motor neurons begin in the spinal cord and brain stem and innervate the muscles throughout the body

35
Q

True or false: men are more likely to develop MND than women?

A

True

36
Q

What is the typical age of MND onset?

A

late middle age, peak 60-70 years

37
Q

What is the mean duration of survival for individuals diagnosed with MND?

A

3 to 5 years

38
Q

True or false: most cases of MND are familial?

A

False: most are sporadic (around 90%)

39
Q

What is one of the first genes identified that, when mutated, increases risk of developing familial MND?

A

mutations in Cu/Zn superoxide mismutase (SOD1)

40
Q

what mutations in which gene accounts for around 40% of familial MND cases?

A

expanded hexanucleotide repeat (GGGGCC) in C9ORF72

41
Q

Other than SOD1 and C9ORF72, which other mutations have been identified associated with familial MND?

A

mutations in DNA/RNA-binding proteins:
TAR DNA binding protein (TDP-43) and Fused in sarcoma (FUS

42
Q

What are three environmental risk factors of MND?

A
  1. consumption of beta-methylaminoalanine (BMAA)
  2. exposure to pesticides
  3. exposure to viruses
43
Q

Give three occupations that are risk factors for MND?

A

professional athletes

served in the military

farmers

44
Q

Give three lifestyle risk factors of developing MND?

A
  1. head trauma
  2. smoking
  3. diet/obesity
45
Q

What evidence suggests that glutamate excitotoxicity may have a pathological role in MND?

A

elevated levels of glutamate have been found in CSF and serum of those with MND

treatment with glutamate antagonist Riluzole delays disease progression

46
Q

What factors may contribute to the development MND?

A

glutamate excitotoxicity
failure of UPS
mitochondrial dysfunction
oxidative damage

47
Q

Describe the pathology of MND

A

degeneration and loss of motor neurons with astrocyte gliosis

intraneuronal inclusions
- main component in the pathology is TDP-43 but may also see ubiquitin deposits, Bunina bodies, SOD1 or FUS aggregates, poly-(Gly-Ala), poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide repeat proteins in C9orf72

48
Q

What is the most common protein aggregate observed in intraneuronal inclusions in MND?

A

TDP-43

49
Q

What are the two approved treatments for MND?

A

Riluzole and Edaravone

50
Q

What is Riluzole and what does it do for treatment of MND?

A

a glutamate antagonist so targets excessive glutamate in excitotoxicity that delays death or time to tracheostomy

51
Q

What is Edaravone and what does it do for treatment of MND?

A

an antioxidant and free-radical scavenger that delays motor deterioration

52
Q

What are potential targets in the pipeline for MND treatment?

A
  • reduce oxidative stress and mitochondrial dysfunction
  • reduce excitotoxicity
  • reduce neuroinflammation (astrogliosis)
  • apoptosis and stem cell therapies - replace the motor neuron
  • nucleocytoplasmic transport
  • DNA damage and RNA splicing/metabolism
53
Q

polymorphisms in which gene encoding an anti-inflammatory protein is a risk factor for AD, MND and PD?

A

TREM2

54
Q
A

BIOL354: Pathobiology (10 decks)

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