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Molecular Neuroscience II > 8 - Huntington's Disease > Flashcards

8 - Huntington's Disease Flashcards

1
Q

What are characteristics of postmortem Huntington’s patient’s brains? (4)

A
  • Atrophy - Fibrillary astrocytosis in basal ganglia and neocortex - GABA-ergic spiny projection neuron degeneration in the striatum - Indirect projections to the external globus pallidus
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2
Q

The visible symptoms of Huntington’s disease correlates with what?

A

Degree of striatal neuron lossStriatum partly responsible for movement

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3
Q

Which gene was Huntington’s disease found to be liked to? What type of DNA marker what this linked to?

A
  • Mutation in the Interesting transcript 15 (IT15) gene (on chromosome 4) - Anonymous polymorphic DNA marker
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4
Q

What is the mutation on IT15 for Huntington’s disease?

A

Expanded CAG trinucleotide repeats in a gene coding for a large multidomain protein with multiple functions named Huntington

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5
Q

Why is Huntington’s disease said to be a PolyQ disease?

A

The trinucleotide repeat that is expanded is CAG (codes for glutamine, aka Q)

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6
Q

Are PolyQ diseases dominantly or recessively transmitted?

A

Dominantly

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7
Q

What are 5 arguments against Huntington’s disease screening?

A
  • There is no treatment - Increased number of suicide attempts - Life insurance problems - Discrimination among siblings - Pro-abortional procedureThese all contribute to the fact that screenings are rarely performed
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8
Q

What are the clinic symptoms of Huntington’s in the early stage and late stage?

A

Early: Subtle psychomotor dysfunctionLate (Manifest progressive disease) - Chorea - Motor impairment - Continued psychomotor dysfunction (increase in severity)

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9
Q

6 out of ______ people in North America, Europe and Australia have Huntington’s

A

6 out of 100,000

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10
Q

True or false? Knockout of the Huntington gene is lethal

A

True

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11
Q

What might the function of Huntington protein be?

A

Synaptic release and vesicular recycling

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12
Q

How many CAG repeats is normal and healthy?

A

20 is normalup to 27 is healthy27-35 CAG repeats are considered mutable normal alleles (Not associated with disease, but could possibly transmit disease into offspring)

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13
Q

How many CAG repeats are nereded to observe pathological effects of Huntington’s disease?

A

36-40 glutamine repeatsComplete penetrance at 40 repeats

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14
Q

What are mouse models of Huntington’s disease based on?

A

Human version of the geneExpressing entire mutated gene (PolyQ Htt gene) in yeast artificial chromosomes (YACs) - Knock in

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15
Q

Phosphorylation of Htt protein leads to?

A

Reduced toxicity of Huntington’s aggregates This results in less degeneration in hippocampus and cerebellum. Growth was seen in the cerebellum

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16
Q

What is observed when Huntington protein migrates into the nucleus of neurons?

A

Activates some transcription factors like peroxisome proliferation and causes accumulation of Huntington’s aggrogates

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17
Q

How are neuronal defence mechanisms decided for defense against Htt proteins?

A

Ubiquitin proteins

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18
Q

What are the three most popular types of neuronal defense against Htt?

A
  • Macro-autophagy (Lysosome) - Proteasomal degradation - Chaperone-mediated refolding - Chaperone-mediated autophagyIn the beginning of the disease, these mechanisms are sufficient
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19
Q

What are the two inclusion types of mutant Huntington? Which is more pathologically aggressive?

A
  • Globular (more aggressive)

- FIbrillar

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20
Q

What is one way to treat Huntington’s at the N17 domain?

A

Phosphorylation will prevent aggregating of fibrillar Huntington protein fragment

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21
Q

How can mutated Htt protein drive apoptosis at the mRNA level?

A

By being spliced with dicer

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22
Q

What is Glutathione known to do?

A

Combat oxidative stress from respiration

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23
Q

What does the only Huntington’s drug do?

A

Inhibits the Vesicular transporters for catecholamines

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24
Q

Name 4 PolyQ diseases

A
  • Huntington’s disease
  • Kennedy disease
  • Dentatorubral-pallidoluysian atrophy
  • Some spinocerebral ataxias
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25
Q

What are HEAT repeats?

A

The repeats of about 50 amino acids that forms the majority of Huntingtin (HTT) protein

HEAT repeat proteins mediate protein-protein interactions in cytoplasmic and nuclear transport, microtubule dynamics and chromosome segregation.

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26
Q

Where is the polyglutamine (polyQ) stretch located in Huntingtin?

A

At the N terminus

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27
Q

How can toxic N-terminal fragments be made from Huntingtin? Name two of them

A

Proteolytic cleavage by caspase 6 at the polyQ stretch on the N terminus

  • cp-1
  • cp-2
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28
Q

What can post-translational modifications (eg. acetylation phosphorylation and addition of small ubiquitin-like modifiers (SUMO)) do to Huntingtin?

A

Alter its cell biology and toxic effects

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29
Q

What are the two amino acid cleavage sequences on HTT?

A
  • IVLD
  • NLPR

Amino acid cleavage sequences

30
Q

What are some suspected functions of HTT?

A
  • Nuclear transport
  • Vesicle transport
  • regulation of RNA trafficking and regulation of gene transcription
  • Early embryonic development
31
Q

How does age affect Huntington’s disease?

A

The older you are, the less number of CAG repeats you need to get the disease.

32
Q

What indicates that CAG repeats are generated more often during spermatogenesis?

A

Juvenile onset of HD is more often transmitted from fathers

33
Q

What are two proposed methods for the generation of CAG repeat expansions?

A
  • Homologous recombination

- Slippage during dysfunctional DNA

34
Q

What is prodromal Huntington’s Disease?

A

PreA and PreB, when pathological process has started but is not clinically manifested

35
Q

What was the first transgenic model of Huntington’s disease?

A

R6/2 mouse, it expresses exon 1 of human Huntington disease gene, containing 150 CAG repeats.

36
Q

What is the N171-82Q mouse?

A

A mouse model for Huntington’s Disease

It is characterised by first 171 amino acid residues from huntingtin protein and 82 glutamines (Q) form the N terminus. Truncated N terminus of human Htt (N171).

  • Shows reduced lifespan to 5-6 months
  • Decreased body size
  • Abnormal gait
  • Bradykinesia
  • Impaired coordination
  • Tremor
  • Neurodegeneration is observed in hypothalamic areas and nuclear inclusions made of Htt and neuritic Htt aggregates are present in the cortex and striatum
37
Q

What key pathological and behavioural trademarks of Huntington’s disease have been replicated in mouse models of the disease? (6)

A
  • Age-dependent disease progression
  • Intranuclear inclusions
  • Overt neurodegeneration
  • Motoric deficits
  • Premature death

All with a strong correlation between polyQ expansion length and disease severity

38
Q

Homozygous Htt null mice show what?

A

Mice with Htt-KO are embryonic lethal, suggesting that Htt is essential for development and survival. Heterozygous KO mice are viable and normal

39
Q

Describe the R6/1 and R6/2 lines of transgenic mice

A

The 5’ end of the human Htt gene carrying 155-150 CAG repeat expansions were developed. Progress of disease in these mice correlates with number of PolyQ.

  • Hemizygous R6/1 mice express a 116 CAG repeat expansion at 12 weeks of age and show neuronal intranuclear inclusions in striatum and cortex
  • Abnormal striatal morphology
  • Abnormal spatial learning
  • Impaired motor coordination
40
Q

What do hemizygous R6/2 mice show?

A

express a 144 CAG repeat expansion

  • Functional and cognitive impairment is visible at 3 weeks, a full Huntington’s disease like phenotype is present by 9-11 weeks and premature death at 10-13 weeks
41
Q

What type of mouse models have been given the full human Htt gene? What is the advantage of this?

A

Mouse models expressing the full Htt gene have been developed using YAC constructs, including normal Htt with 18 CAG repeats and mutant Htt with 46, 72 and 128 CAG repeat expansions.

  • Markers of excitotoxicity similar to human patients were detected in YAC128 mice
  • BAC transgenic mice containing the full Htt genes were developed.

The advantage is strong correlation between polyQ expansion length and disease severity

42
Q

Describe Htt knock-in mice

A

A model with 150 polyQ expansion at the age of 13 months exhibited reduced body size and gliosis, but without evidence of brain atrophy or neurodegeneration.
- htt knock-in mice are considered a most faithful model because of their proper location within the genome

43
Q

Which Huntington’s Disease mice model is considered the most faithful model? Why?

A

Htt knock-in mice

Because of their proper location within the genome

44
Q

List the four types of Huntington’s Disease model mice and something unique about each.

A
  • N171-82Q (die in 5-6 months, abnormal gait and impaired coordination)
  • R6/1 and R6/2 (deat at 10-13 weeks)
  • YAC128 and BAC Htt mice (markers of excitotoxicity)
  • Htt Knock in Mice (at 13 months, show reduced body size and gliosis, but no evidence of brain atrophy or neurodegeneration)
45
Q

The level of degeneration in YAC mouse models was reverse correlated with ____?

A

The ratio of phosphorylated Htt over total Htt in the striatum, globus pallidus and cortex.

That is, phosphorylation seemed to protect against degeneration.

46
Q

What is the consequent of mutant Htt cleavage by caspase 6? (3)

A
  1. Mutant Huntingtin is cleaved by caspase 6, generating toxic fragments with abnormal compact β conformation
    - Toxic fragments can inhibit chaperones, proteasomes and autophagy.
    - This can lead to abnormally folded proteins and other cellualr constituents.
47
Q

The toxic fragments generated from the cleaving of mutant Htt by caspase 6 inhibit what three intracellular components? What is the consequence of this?

A
  • Chaperones
  • Proteasomes
  • Autophagy

This can lead to abnormally folded proteins and other cellualr constituents.

48
Q

How might mutant Htt affect the mitochondria?

A
  • Decreasing ATP production
  • Increasing synthesis of reactive oxygen species (ROS)
  • Interaction with gene transcription via PGC1α, leading to decreased transcription of BDNF and nuclear-encoded mitochondrial proteins
49
Q

What is the PGC1α gene? (what does it stand for, what type of gene is it, what two effects does it have with mutant Htt)

A
  • Peroxisome proliferator-activated receptor gamma coactivator 1-α
  • Transcriptional coactivator regulating gene involved in energy metabolism
  • PGC1α-KO and mutant Htt induce neuronal dysmyelination.
  • Interaction of mutant Htt may interact with HAP1 (Huntingtin associated protein 1), disrupting the endocytosis process
50
Q

What are four methods for neuronal defence mechanisms against Huntington’s disease?

A
  • Proteasomal degradation of mutant Htt
  • Chaperone mediated refolding
  • Chaperone mediated autophagy
  • Macroautophagy
51
Q

How can globular mutant Htt fragments be formed?

A

Soluble Htt exon1 with a CAG expansion beyond 37 repeats adopts an open conformation, pushing N17 domain and polyproline out of alignment, possibly triggering protein aggregation

52
Q

How can fibrillar mutant Htt fragments be formed? What is the way to induce this therapeutically?

A

The N17 domain is phosphorylated, causing tightly-packed protein deposits that do not exchange with soluble phase, this seems protective in HD.

Ganglioside GM1 induces phosphorylation of mutant Htt and restores normal motor behaviour in HD mice.

53
Q

What is BDNF?

A

Brain derived neurotrophic factor

A canonical nerve growth factor.

54
Q

What does mutant Htt do in the cortico-striatal neurons? (5)

A
  • Decreased transport
  • Release of BDNF
  • Induces glutamate release (excitotoxicity)
  • Reduces uptake of Glu by astrocytes (excitotoxicity)
  • Activated microglia
55
Q

What is the microglial response to mutant Htt?

A

Production of inflammatory agents and 3-hydroxykynurenine, which stimulate production of reactive oxygen species (ROS) and cause oxidative stress

56
Q

What are sCAGs? What do they do?

A

small CAG repeated RNAs (from expanded Htt exon-1 mRNA with CAG repeat lengths above the threshold (40)

sCAGs are incorporated into the RISC and trigger abnormal gene silencing, leading to neurotoxicity.

57
Q

How are antisense oligonucleotides being used as therapy for Huntington’s disease?

A

DNA-like antisense nucleotides target mutant Htt mRNA transcript and form RNA-DNA hybrids. These hybrids become a target of RNase H

RNase H cleaves RNA, leaving antisense DNA oligonucleotide intact, which can bind another target RNA

58
Q

How have RNAi therapies been used to treat Huntington’s disease? (3)

A
  • The mutant transcript can be targeted selectively without affecting non-mutant transcripts.
  • siRNA therapies can also be potent since delivery of a relatively small amount of trigger (drug) could have a persistent effect on gene silencing because RNAi is reiterative
  • Ago2 protein is multiple turnover enzyme such that each small RNA directs cleavage of hundreds of target mRNA molecules
59
Q

How can mitochondrial damage be prevented in HD150-knock-in Huntington’s disease model mice?

A

Chronically administered XJB-5-131 antioxidant

Can restore mDNA abundance back to control levels

60
Q

What are intrabodies and how are they made?

A

Recombinant antibody molecules obtained by cDNA cloning of the antigen binding domain.

The variable heavy and light chains (Vh and Vl) from the antibody are then joined together by a synthetic cDNA encoding a polypeptide linker. Intrabodies can target antigens intracellularly

61
Q

How can intrabodies treat Huntington’s disease?

A

The anti-huntingtin scFv intrabody reduces buildup of abnormal protein aggregates in vitro

62
Q

How can neurodegeneration in a Drosophila Huntington’s Disease model by counteracted with intrabodies?

A

The C4 sFv anti-huntingtin intrabody completely rescued elaborate eclosion behaviour (emerging from pupal case), which requires precisely timed and coordinated motor output, triggered through the complex interaction of the nervous system with both steroid and neuropeptide hormones

63
Q

True or false? Intrabody treatment for Huntington’s disease prevents mutant Htt aggregate buildup only when administered early in the organisms life?

A

False, the efficiency of intrabody treatment on reducing aggregates was only slightly reduced when compared to early injections

64
Q

How can quinolinic acid be used to induce Huntington’s disease model in mice?

A

It is an NMDA receptor agonist, excitotoxicity induces lesions. When administered to the striatum, these lesions can mimic HD

65
Q

How can neural tissue grafts be used to treat Huntington’s disease? (1 method, 3 results)

A
  • Human forebrain and spinal GABA neurons were transplanted into the striatum of quinolinic acid-lesioned mice (HD model).
  • This resulted in generation of GABA neuron populations co-expressing DARPP32+ (a feature of striatal medium spiny neurons - the ones that HD degenerates)
  • These neurons projected to the substantia nigra and received connections from glutamatergic and dopaminergic inputs
  • The grafts rescued motor deficits in quinolinic acid-lesioned mice
66
Q

What might explain slow migration times for grafted neurons?

A

Neural precursor cells secreting receptor tyrosine kinase ligands:

  • Fibroblast growth factor-2 (FGF2)
  • Vascular endothelial growth factor (VEGF)

These chemoattractants for neurons may be slowing migration of grafted neural tissue

67
Q

What does nintedanib (BIBF 1120) do?

A

An antagonist of

  • fibroblast growth factor-2 (FGF2) and vascular
  • endothelial growth factor (VEGF),
  • Platelet derived growth factor receptor (PDGFR)

This stimulates migration of neural precursor cells, which indicates that this antagonist may be applied when using neural grafts for Huntington’s disease treatment.

68
Q

Knockout of mGluR5 in Huntington’s disease mice shows what? What do mGlur5 antagonists show?

A

Huntingtin (EM48) intranuclear inclusions are reduced (good thing)

mGluR5 antagonists increased locomotor activity in control and Huntington’s disease knock-in mice. mGlur5 antagonists may have a neuroprotective effect as well as improve the motor system.

69
Q

What are glutathione peroxidases?

A

Antioxidant enzymes that catalyze the reduction of hydrogen peroxide and lipid hydroperoxides in Huntington disease flies (Htt93Q)

70
Q

Overexpression of mouse GPx1 (glutathione peroxidase 1) does what?

A

Counteracts the loss of rhabdomeres in the ommatidia and restored locomotor activity in Huntington’s disease flies.

Both transgenic mGPx and ebselen (similar to GPx’s) did not affect autophagy, a process which is important for clearance of misfolded Htt.

Molecular Neuroscience II (7 decks)

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