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MD4001 > Molecular basis of molecular disease > Flashcards

Molecular basis of molecular disease Flashcards

1
Q

What is a trinucleotide repeat?

A

• A series of 3 bases repeated consecutively, they can occur anywhere throughout a gene

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2
Q

Name a syndrome that occurs as a result of a trinucleotide repeat in the 5’ untranslated region

A

Fragile X syndrome

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3
Q

Name 2 syndromes that occur as a result of a trinucleotide repeat in the exonic region

A
  • Huntington’s

* Spinobulbar muscular atrophy

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4
Q

Name a syndrome that occurs as a result of a trinucleotide repeat in the 3’ untranslated region

A

Myotonic dystrophy

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5
Q

Describe the presentation of Huntington’s disease

A
  • Autosomal dominant
  • Presentation begins in midlife (40s-50s)
  • Motor abnormalities
  • Behavioural and psychiatric changes
  • Gradual loss of cognition
  • Ultimately, death
  • 1/3 present with psychiatric abnormalities, 2/3 have a combination of cognitive and motor disturbances
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6
Q

Describe the effect on the brain of Huntington’s

A
  • Striatum severely affected
  • Atrophy of the caudate nucleus and putamen
  • Trinucleotide repeat in the coding region (exon) - polyglutamine
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7
Q

Why is the insertion of glutamine harmful?

A
  • Protein misfolds
  • The R group in glutamine is an amine conformation, this means there is increased hydrogen bonding giving it lots of strength, causing it to misfold and aggregate
  • Inclusion bodies
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8
Q

What are the ethical issues surrounding Huntington’s?

A
  • Usually occurs after the reproductive years
  • no cure
  • Does an asymptomatic at risk individual have a duty to undergo testing before reproducing
  • Is it ethical to allow asymptomatic children from families with Huntington’s to get tested
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9
Q

What is fragile x syndrome?

A
  • Single gene disorder on the X chromosome
  • Affects males and females of all ages and all ethnicities (slightly more common in males, females tend to have more mild symptoms)
  • ‘fragile’ site Xq27.3
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10
Q

What is the fragile X phenotype?

A
  • Long face, prominent jaw and forehead
  • mitral valve prolapse
  • Attention deficit/hyperactivity disorder
  • Autistic like behaviour: tactile defensive, poor eye contact, hand flapping
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11
Q

Describe the molecular cause of fragile X syndrome

A
  • Mental retardation gene 1 FMR1
  • Tri-nucleotide repeat in the non coding region
  • Less mRNA produced means less protein produced
  • Expansion results in transcriptional silencing
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12
Q

What is the function of the FMR1 gene?

A
  • Highly expressed in neurones
  • Regulates mRNA translation in dendrites
  • Usual function of FMRP is to repress the translation of proteins stimulated by the glutamate pathway, without this, more protein is produced
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13
Q

When is DNA unwound?

A
  • Replication
  • Recombination
  • DNA repair
  • Transcription
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14
Q

What is genetic anticipation

A

As a genetic disorder is passed down from generation to generation, the symptoms of the genetic disorder become more apparent/worse

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15
Q

Why does genetic anticipation occur?

A
  • As the DNA is unwound, there is an increased instability

* The more repeats, the more unstable it is and therefore the more unstable are the somatic cells

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16
Q

How does genetic anticipation help clinically?

A
  • Diagnosis of condition
  • Genetic counselling
  • Potentially treatable
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17
Q

What is RG6042?

A
  • A molecule deigned to target the underlying molecular cause in Huntington’s
  • It is an antisense oligonucleotide - RNA is synthesised that is complimentary to the mRNA of the mutant protein
  • When it binds, it forms a hybrid that is degraded
  • It works because it will only bind to the abnormal form
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18
Q

Describe the spread of Alzheimer’s disease in the brain?

A

Starts in the entorhinal cortex and progresses to the hippocampus then the cerebral cortex

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19
Q

What is APP?

A
  • Amyloid precursor protein
  • Normally concentrated in neurones
  • Regulates synapse formation
20
Q

What is the significance of APP in early onset Alzheimers?

A
  • Normal cleavage of APP is by alpha-secretase
  • If cleaved by beta secretes, it produces an AB peptide which accumulates and forms an oligomer peptide
  • APP mutations increase Beta secretase cleavage
21
Q

What is the effect of PSEN1/2 mutations

A

• Increase gamma secretase cleavage of APP

22
Q

In sporadic Alzheimers, what is the protein thought to have an impact on risk of developing Alzheimers?

A
  • APOE
  • 3 alleles - E2, E3, E4 - each differ by one amino acid
  • Heterozygous for E4 have a 3 fold risk
  • Homozygous for E4 have a 15 fold risk
23
Q

What is the role of APOE?

A
  • Cholesterol transport

* Clears amyloid Beta

24
Q

What my occur as a result of the breakdown of APOE E4?

A

Toxic products get generated

25
Q

How can you find implicated genes in a disease?

A
  • Examine DNA to find single nucleotide polymorphisms

* Compare SNPs of a group affected by the disease to SNPs of a group who are not affected

26
Q

Which genes are implicated in Alzheimers?

A
  • APP
  • APOE
  • Clusterin
  • PICALM
  • CR1
  • PSEN 1/2
27
Q

What are neurofibrillar tangles?

A

Tangles arise due to problems with phosphorylation of TAU (hyperphsophorylated)

28
Q

What is the role of tau?

A

Stabilises microtubules

29
Q

What are tau mutations associated with?

A

Frontal-temporal dementia

30
Q

What can be done therapeutically for Alzheimers?

A
  • Secretase inhibitors
  • Prevents phosphorylation of Tau
  • Aggregation inhibitors (Tau and AB)
  • Statins
31
Q

What are prion diseases?

A

Transmissible spongiform encephalopathy

32
Q

Name 3 prion diseases

A
  • Creutzfeld- Jakob disease
  • Fatal familial insomnia (inherited)
  • Kuru (usually rare, acquired form prevalent in papa New Guinea because of cannibalism)
33
Q

What are the symptoms of prion diseases?

A
  • Confusion and forgetfulness
  • Progression to severe depression and ataxia
  • Eventually leads to death
34
Q

What are the percentages for the different acquisitions of prion diseases?

A
  • Inherited: 10-15%
  • Sporadic: 85%
  • Acquired: Normally rare
35
Q

Describe the spongiform pathology

A
  • Spongy vacuoles form where neurones have died
  • Increased activation of astrocytes
  • Results in scarring, deposition of prions and plaque formation
36
Q

What is a prion?

A
  • Proteinaceous: only contains protein material which is resistant to heat and disinfectants
  • Infectious
  • Has no genetic material
37
Q

Why are prions infectious?

A
  • Everyone expresses a prion protein
  • Normally this is prion protein conformation C
  • it has various beta sheets and alpha helices
  • The variant form adopts a different conformation: PRP SC which is much more rich in beta sheets
  • It is hard to raise an immune response to it and it often avoids detection by the immune system
38
Q

What is prion propagation

A
  • Conversion of normal PRP C to SC

* Causes it to accumulate

39
Q

Cell to cell transmission of PRP^SC

A
  • When it has accumulated, it can travel by exocytosis and endocytosis to different cells
  • Can be deposited in amyloid toxic- like fibres, killing the neurone causing astrocytes to invade and remove the dead neurones, leaving the spongy holes
40
Q

What is the normal function of PRP

A
  • 2 copies
  • Anchored to GPI group which allows it to be embedded in the neuronal membrane - particularly the synaptic membrane
  • Glycosylated
  • Mice lacking in PRP behave normally but have altered circadian rhythms and sleep patterns
  • not really sure basically
41
Q

What are the prospects for therapy of Prion diseases?

A
  • Stabilising PRP c
  • Clearance of PRP sc
  • Vaccination against PRP sc
42
Q

what is the age of infection with vCreutzfeld Jakob Disease?

A

19-39

43
Q

What is the age of infection of sporadic prion disease?

A

55-70

44
Q

What is the usual duration of Creutzfeld Jakob disease?

A

7.5-22 months

45
Q

What is the usual duration of sporadic prion disease?

A

2.5-6.5 months

MD4001 (28 decks)

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