2. Molecular basis of some neurological disorders

Question 1

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

Answer 1

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

Question 2

CAG base sequence codes for…

Answer 2

Glutamine (NOT EXCESS GLUTAMATE)

Question 3

DNA cause of huntingtons?

Answer 3

Trinucleotide repeat in the coding region.

Polyglutamine in coding region (exon): protein altered

Question 4

Why is insertion of extra glutamine residues harmful?

Answer 4

• Protein misfolds
• Aggregates due to a more “beta sheet” like structure as the R groups of gluamine (amino acid) interact.
• Inclusion bodies

Question 5

Fragile X syndrome;
Leads to?
Epidemiology?
Phenotype
Cause?

Answer 5

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

Question 6

How does hairpin confirmation form?

Answer 6

Bonds between bases of same strand, not opposite

Question 7

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

Answer 7

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

Question 8

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

Answer 8

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

Question 9

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

Answer 9

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

Question 10

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

Answer 10

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

Question 11

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

Answer 11

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

Question 12

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

Answer 12

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

Question 13

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

Answer 13

Working copies = expansions of repeats

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

Question 14

Alzheimer’s disease histology?

Answer 14

Tangle in neurones

Plaques

Question 15

Severe Alzheimer’s structural impact?

Answer 15

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

Question 16

Dominance of AD?

Answer 16

Autosomal dominance

Question 17

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

Answer 17

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

Question 18

Common early onset AD genetic mutations?

Role of gene in normal?

Answer 18

Mutations in **presenilin1 *** and presenilin 2

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

Question 19

Genetic cause of sporadid AD?

Answer 19

• 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

Question 20

Role of ApoE?

Answer 20

Involved in cholesterol transport.
Clears amyloid beta

Hence Breakdown of apoE e4 might generate toxic products

Question 21

Sporadic AD genetic mutations?

Answer 21

Clusterin
PICLAM
CR1
ApoE

Question 22

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

Answer 22

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

Question 23

How are neurofibrillar tangles related to plaques?

Answer 23

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

Question 24

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

Answer 24

Tau mutations

Question 25

What therapeutic mechansims help to reduce AD symptoms?

Answer 25

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

Question 26

Prior disease, inherited or sporadic?

Answer 26

sporadic (85%)

Question 27

Prion diseases lead to _________ _________ encephalopathy

Answer 27

Prion diseases lead to Transmissible spongiform encephalopathy

Question 28

What is a prion?

Answer 28

Infectious form of protein, no genetic material

Question 29

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

Answer 29

Coverts it to infectious.

Allows small amount of infection to accumulate rapidly

Question 30

Normal function of PRPN? (non infectious prion)

Answer 30

• GPI-anchor
• Glycosylated
• Synaptic membranes of neurons

Question 31

What is CFD?

Answer 31

Creutzfeld-Jakob Disease

Question 32

Main example of prion diseases

Answer 32

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

Question 33

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

Answer 33

vCJD:
19-39yrs
7.5-22 months

Sporadic CJDL

• 55-70yrs
  2. 5-6.5 months

Question 34

Role of the FMRP?

Answer 34

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

Protein lost in Fragile X syndrome