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MD4001 Week 5 > 2. Molecular basis of some neurological disorders > Flashcards

2. Molecular basis of some neurological disorders Flashcards

1
Q

Huntington’s disease/ chorea:
Dominance?
Presentation progression
Location affections?

A 
Autosomal Dominant (~1/25,000, although this varies by ethnic group)
Presentation begins in midlife – motor abnormalities (chorea and dystonia), behavioral and psychiatric changes, gradual loss of cognition and ultimately death

~1/3 of patients present with psychiatric abnormalities; 2/3 have a combination of cognitive and motor disturbances

Striatum most severely affected
Atrophy of the caudate nucleus and putamen

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2
Q

CAG base sequence codes for…

A

Glutamine (NOT EXCESS GLUTAMATE)

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3
Q

DNA cause of huntingtons?

A

Trinucleotide repeat in the coding region.

Polyglutamine in coding region (exon): protein altered

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4
Q

Why is insertion of extra glutamine residues harmful?

A
  • Protein misfolds
  • Aggregates due to a more “beta sheet” like structure as the R groups of gluamine (amino acid) interact.
  • Inclusion bodies
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5
Q 
Fragile X syndrome;
Leads to?
Epidemiology?
Phenotype
Cause?
A

Leading cause of inherited mental impairment

Men and women of all ages and ethnicity. More women

Cause:
Caused by CGG expansion at the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene.
Result in a block of transcription and absence of the fragile X mental retardation protein (FMRP).
The lack of FMRP (key for mRNA metabolism in the brain) is thought to be the direct cause of the FXS phenotype.

Phenotype:
• Long face - prominent forehead & jaw
• Mitral valve prolapse
• Mental impairment (I.Q. 20-60)
• Attention deficit / hyperactivity disorder
• Autistic-like behavior – tactile defensive,poor eye contact, hand-flapping

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6
Q

How does hairpin confirmation form?

A

Bonds between bases of same strand, not opposite

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7
Q

Triplet repeats associated with human disease can adopt ______ _________ in vitro at physiological salt levels and temperatures

A

Triplet repeats associated with human disease can adopt hairpin conformations in vitro at physiological salt levels and temperatures

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8
Q

What is the mechanism of expansion of the trinucleotide repeats?again

A

Polymerase stutters and gets confused around trinucleotide repeat. . On first round of replication the hairpin forms, on second round the repeat is incorporated into the DNA with the expansion between repeats.

Hence making disease worse

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9
Q

How does the number of repeats vary in normal, mild and affected Huntington’s disease patients?

A

Presentation:
Normal =28 or less
Mild/carrier = 29-39
Affected = 40 +

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10
Q

How does the number of repeats vary in normal, mild and affected Fragile X syndrome patients?

A

Presentation:
Normal =6-54
Mild/carrier = ~60-200
Affected =230 +

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11
Q

How does the number of repeats vary in normal, mild and affected Myotonic dystrophy patients?

A

Presentation:
Normal =5-35
Mild/carrier = 50-500 (classical)
Affected = !000+ (congenitial)

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12
Q

As gene is passed from one generation to other there is an ________ in number of repeats and severity of disease. This is genetic _______

A

As gene is passed from one generation to other there is an increase in number of repeats and severity of disease. This is genetic anticipation

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13
Q

Effect of number of copies of working genes on the repeat expansion?

A

Working copies = expansions of repeats

Note on RHS there are no working copies and therefore NO expansions

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14
Q

Alzheimer’s disease histology?

A

Tangle in neurones

Plaques

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15
Q

Severe Alzheimer’s structural impact?

A

Severally enlarged ventricles
Extreme shrinkage of cerebral cortex
Extreme shrinkage of cortex
Extreme shrinkage of the hippocampus

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16
Q

Dominance of AD?

A

Autosomal dominance

17
Q

How is APP (amyloid precursor protein) cleavage involved in AD?

A

Normally APP is cleaved by alpha-secretase.

APP mutations lead to increase cleavage of APP via beta-secretase
PSEN1/PSEN2 mutations also increase APP cleave via gamma-secretase
–> Excess amyloid-beta peptide accumulation –> Formation of oligomer aggregate

18
Q

Common early onset AD genetic mutations?

Role of gene in normal?

A

Mutations in **presenilin1 *** and presenilin 2

Role: Affect the activity of the g-secretase enzyme complex

19
Q

Genetic cause of sporadid AD?

A 
• ApoE
Sporadic AD
• 3 alleles e2, e3 and e4 differ by single amino acid
• Heterozygotes for e4 3 fold risk
• Homozygotes for e4 15 fold risk
• NOT certainty
20
Q

Role of ApoE?

A

Involved in cholesterol transport.
Clears amyloid beta

Hence Breakdown of apoE e4 might generate toxic products

21
Q

Sporadic AD genetic mutations?

A

Clusterin
PICLAM
CR1
ApoE

22
Q

Difference between familial and sporadic causes of Alzheimers disease?
Overall both do….

A

Familial:

  1. APP mutations, trisomy 21
    - APP cleavage mutation via beta-secretase
  2. PS1, PS2 mutations
    - APP cleavage mutation via gamma-secretase

Sporadic:
-ApoE, CLU, PICALM, CR1

BOTH CAUSE A-beta oligomer formation which causes synpatic loss and neuronal death by….

  • Amyloid senile plaques
  • LTP impairment
23
Q

How are neurofibrillar tangles related to plaques?

A

Protein Tau becomes phosphorylates, microtubules destabilised and form paired tangles.

24
Q

Fronto-temporal dementia with parkinsonism (no plaques), cause?

A

Tau mutations

25
Q

What therapeutic mechansims help to reduce AD symptoms?

A
  • Secretase inhibitors
  • Prevent phosphorylation of Tau
  • Aggregation inhibitors (both Tau and Ab)
  • Statins to interfere with cholesterol
  • Immunization
26
Q

Prior disease, inherited or sporadic?

A

sporadic (85%)

27
Q

Prion diseases lead to _________ _________ encephalopathy

A

Prion diseases lead to Transmissible spongiform encephalopathy

28
Q

What is a prion?

A

Infectious form of protein, no genetic material

29
Q

When infectious protein form comes into contact wit (PRPsc) h normal form (PRPc)…

A

Coverts it to infectious.

Allows small amount of infection to accumulate rapidly

30
Q

Normal function of PRPN? (non infectious prion)

A
  • GPI-anchor
  • Glycosylated
  • Synaptic membranes of neurons
31
Q

What is CFD?

A

Creutzfeld-Jakob Disease

32
Q

Main example of prion diseases

A

• Transmissible spongiform encephalopathy
– Creutzfeld-Jakob Disease (CJD)
– Fatal familial insomnia
– Kuru

33
Q

Difference between variant CFD and sporadic CJD:
Age?
Duration?

A

vCJD:
19-39yrs
7.5-22 months

Sporadic CJDL

  • 55-70yrs
    2. 5-6.5 months
34
Q

Role of the FMRP?

A

Fragile X Mental Retardation Protein
Regulates mRNA translation in dendrites
Is HIGHLY expressed in neurones

Protein lost in Fragile X syndrome

MD4001 Week 5 (11 decks)

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