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MD4001 Pathology > Molecular Basis of Some Neurodegenerative Disorders > Flashcards

Molecular Basis of Some Neurodegenerative Disorders Flashcards

1
Q

What is a trineucliatide repeat?

A

Series of 3 bases which is repeated consequetively

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2
Q

What are different types of trinucleotide repeat disorders?

A
  • Huntington’s
  • Spinobulbar muscular atrophy
  • Dentatorubral-Pallidoluyslan atrophy
  • Spinocerebellar Ataxia (many different types)
  • Machado-Joseph Disease (SCA3)
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3
Q

When does huntington’s disease usually present?

A

Midlife - motor abnormalities (chorea and dystonia), behavioural and psychiatric changes, gradual loss of cognition and ultimately death

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4
Q

What percentage of patients with huntingtons present with psychiatric abnormalities?

A

33%

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5
Q

What percentage of patients with huntington’s present with a combination of cognitive and motor disturbances?

A

66%

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6
Q

What areas of the brain are affected by huntington’s?

A
  • Striatum (neostriatum)

- Atrophy of the caudate nucleus and putamen

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7
Q

What is chorea?

A

Dancing like movements associated with huntington’s

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8
Q

What does CAG gene code for?

A

Glutamine

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9
Q

What happens when too many glutamines are coded for in huntington’s?

A

Misfolding of huntington protein allows formation of aggregates. Contains inclusion bodies of huntington bodies in both nucleus and cytoplasm of affected individuals.
Beta sheets

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10
Q

What are the ethical issues surrounding HDs?

A
  • No cure
  • Usually occurs after reproductive years
  • Does an asymptomatic at-risk individual have a duty to undergo testing and learn the result before reproducing
  • Is it ethical to allow asymptomatic children from families with HD to be tested
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11
Q

What is the leading cause of inherited mental impairment?

A

Fragile X syndrome

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12
Q

Where is the fragile site in fragile X syndrome?

A

Xq27.3 (single gene disorder)

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13
Q

What group does fragile X syndrome affect the most

A

Males (1 in 4000) twice as many as females

- Affects people of all ages and ethnic groups

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14
Q

What are the features of Fragile-X phenotype?

A
  • Long face - prominant forehead and jaw
  • Mitral valve prolapse
  • Mental impairment (IQ 20-60)
  • Attention deficit / hyperactivity disorder
  • Autistic-like behavior - tactile defensive, poor eye contact, hand flapping
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15
Q

What are the genetics that cause fragile-X syndrome?

A

Fragile X Mental Retardation gene 1 (FMR1)

  • Trinucleotide repeat (CGG) in the 5’ non-coding region
  • Expansion results in transcriptional silencing
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16
Q

What does the FMR1 protein do?

A
  • Highly expressed in neurons
  • Regulates mRNS translation in dendrites
  • Inhibits the translation of other messages which are stimulated by the glutamate pathway
  • In Fragile X syndrome overactivation of glutamate signalling pathway
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17
Q

What abnormal conformations can triplet repeats adopt in vitro when unwound and at physiological salt levels and temperatures?

A

Hairpin conformation

18
Q

What is genetic anticipation?

A

As a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase in the severity of symptoms is also noted

19
Q

What is number of repeats is thought to make a mild/carrier of myotonic dystrophy?

A

50 - 500

20
Q

What number of repeats are thought to cause congenital myotonic dystrophy?

A

> 1000

21
Q

What numbers of repeats are thought to cause fragile X syndrome?

A

> 230 (60-200 in a mild/carrier)

22
Q

What number of repeats are thought to cause Huntingtons?

A

> 40 (29-39 in a mild/carrier)

23
Q

What has been done in animals to prevent the trinucleotide expansion?

A

Removal of DNA mismatch repair genes

24
Q

WHat is RG6042?

A
  • An investigational molecule designed to target the underlying genetic cause of HD
  • Anti-sense oligodendricite
  • Targets expanded CAG
  • Causes mRNA degradation
  • Reduces translation and production of HTT - less protein made
25
Q

What are the characteristics of alzheimer’s disease often seen in post-mortems?

A
  • Plaques - outside cell

- Tangles - inside cell

26
Q

What are tangles made up of?

A

Hyperphosphorylated tau

27
Q

What are plaques made up of?

A

Amyloid Beta

28
Q

What is significant in the pathology of Alzheimer’s which makes treatment difficult?

A

Many molecular changes are happening in the pre-clinical phase - a long time before symptoms

29
Q

In what percentage of people is ALzheimer’s an autosomal dominant inherited disease?

A

~ 5%

30
Q

What protein is associated with both Down’s syndrome and early-onset Alzheimer’s disease?

A

Amyloid Precursor Protein (present on chr21)

31
Q

How can APP cause Alzheimer’s?

A
  • Normally concentrated on neurons where it regulates synapse formation in cell membrane
  • Too much or abnormal APP
  • In process of abnormal cleaving by secratases can result in form of Amyloid Beta peptide being produced that can aggreagate in outside of cell
32
Q

Mutations in what proteins can cause early onset AD?

A
  • Presenilin 1 (70%) and 2 (~5%)

- APP (~25%)

33
Q

WHat do presenilin 1 and 2 affect the activity of?

A

gamma-secretase enzyme complex

34
Q

What is a risk factor for sporadic AD?

A
  • ApoE
  • 3 alleles that differ by just one amino acid
  • Not certainty (can give a 15 fold risk)
35
Q

What does ApoE do?

A
  • Cholesterol transport
  • CLears amyloid B
  • Breakdown of apoE e4 might generate toxic products
36
Q

How can we identify other genes which may be responsible for AD?

A

Comapring patients and nonpatients DNA - then look for disease specific SNPs

37
Q

What other proteins are thought to be involved in AD?

A
  • Clusterin
  • PICALM
  • APOE
38
Q

How do neurofibrillar tangles arise?

A

Changes in the tau phosphorylation assembles in PHF assembly

39
Q

What does tau stabilise?

A

Microtubules

40
Q

What type of dementia has tau mutations that are not associated with plaques?

A

Fronto-temporal dementia

MD4001 Pathology (18 decks)

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