Molecular basis of molecular disease Flashcards
What is a trinucleotide repeat?
• A series of 3 bases repeated consecutively, they can occur anywhere throughout a gene
Name a syndrome that occurs as a result of a trinucleotide repeat in the 5’ untranslated region
Fragile X syndrome
Name 2 syndromes that occur as a result of a trinucleotide repeat in the exonic region
- Huntington’s
* Spinobulbar muscular atrophy
Name a syndrome that occurs as a result of a trinucleotide repeat in the 3’ untranslated region
Myotonic dystrophy
Describe the presentation of Huntington’s disease
- 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
Describe the effect on the brain of Huntington’s
- Striatum severely affected
- Atrophy of the caudate nucleus and putamen
- Trinucleotide repeat in the coding region (exon) - polyglutamine
Why is the insertion of glutamine harmful?
- 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
What are the ethical issues surrounding Huntington’s?
- 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
What is fragile x syndrome?
- 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
What is the fragile X phenotype?
- Long face, prominent jaw and forehead
- mitral valve prolapse
- Attention deficit/hyperactivity disorder
- Autistic like behaviour: tactile defensive, poor eye contact, hand flapping
Describe the molecular cause of fragile X syndrome
- 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
What is the function of the FMR1 gene?
- 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
When is DNA unwound?
- Replication
- Recombination
- DNA repair
- Transcription
What is genetic anticipation
As a genetic disorder is passed down from generation to generation, the symptoms of the genetic disorder become more apparent/worse
Why does genetic anticipation occur?
- 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
How does genetic anticipation help clinically?
- Diagnosis of condition
- Genetic counselling
- Potentially treatable
What is RG6042?
- 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
Describe the spread of Alzheimer’s disease in the brain?
Starts in the entorhinal cortex and progresses to the hippocampus then the cerebral cortex
What is APP?
- Amyloid precursor protein
- Normally concentrated in neurones
- Regulates synapse formation
What is the significance of APP in early onset Alzheimers?
- 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
What is the effect of PSEN1/2 mutations
• Increase gamma secretase cleavage of APP
In sporadic Alzheimers, what is the protein thought to have an impact on risk of developing Alzheimers?
- 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
What is the role of APOE?
- Cholesterol transport
* Clears amyloid Beta
What my occur as a result of the breakdown of APOE E4?
Toxic products get generated
How can you find implicated genes in a disease?
- 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
Which genes are implicated in Alzheimers?
- APP
- APOE
- Clusterin
- PICALM
- CR1
- PSEN 1/2
What are neurofibrillar tangles?
Tangles arise due to problems with phosphorylation of TAU (hyperphsophorylated)
What is the role of tau?
Stabilises microtubules
What are tau mutations associated with?
Frontal-temporal dementia
What can be done therapeutically for Alzheimers?
- Secretase inhibitors
- Prevents phosphorylation of Tau
- Aggregation inhibitors (Tau and AB)
- Statins
What are prion diseases?
Transmissible spongiform encephalopathy
Name 3 prion diseases
- Creutzfeld- Jakob disease
- Fatal familial insomnia (inherited)
- Kuru (usually rare, acquired form prevalent in papa New Guinea because of cannibalism)
What are the symptoms of prion diseases?
- Confusion and forgetfulness
- Progression to severe depression and ataxia
- Eventually leads to death
What are the percentages for the different acquisitions of prion diseases?
- Inherited: 10-15%
- Sporadic: 85%
- Acquired: Normally rare
Describe the spongiform pathology
- Spongy vacuoles form where neurones have died
- Increased activation of astrocytes
- Results in scarring, deposition of prions and plaque formation
What is a prion?
- Proteinaceous: only contains protein material which is resistant to heat and disinfectants
- Infectious
- Has no genetic material
Why are prions infectious?
- 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
What is prion propagation
- Conversion of normal PRP C to SC
* Causes it to accumulate
Cell to cell transmission of PRP^SC
- 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
What is the normal function of PRP
- 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
What are the prospects for therapy of Prion diseases?
- Stabilising PRP c
- Clearance of PRP sc
- Vaccination against PRP sc
what is the age of infection with vCreutzfeld Jakob Disease?
19-39
What is the age of infection of sporadic prion disease?
55-70
What is the usual duration of Creutzfeld Jakob disease?
7.5-22 months
What is the usual duration of sporadic prion disease?
2.5-6.5 months
