Molecular Basis of Some Neurodegenerative Disorders Flashcards
What is a trineucliatide repeat?
Series of 3 bases which is repeated consequetively
What are different types of trinucleotide repeat disorders?
- Huntington’s
- Spinobulbar muscular atrophy
- Dentatorubral-Pallidoluyslan atrophy
- Spinocerebellar Ataxia (many different types)
- Machado-Joseph Disease (SCA3)
When does huntington’s disease usually present?
Midlife - motor abnormalities (chorea and dystonia), behavioural and psychiatric changes, gradual loss of cognition and ultimately death
What percentage of patients with huntingtons present with psychiatric abnormalities?
33%
What percentage of patients with huntington’s present with a combination of cognitive and motor disturbances?
66%
What areas of the brain are affected by huntington’s?
- Striatum (neostriatum)
- Atrophy of the caudate nucleus and putamen
What is chorea?
Dancing like movements associated with huntington’s
What does CAG gene code for?
Glutamine
What happens when too many glutamines are coded for in huntington’s?
Misfolding of huntington protein allows formation of aggregates. Contains inclusion bodies of huntington bodies in both nucleus and cytoplasm of affected individuals.
Beta sheets
What are the ethical issues surrounding HDs?
- 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
What is the leading cause of inherited mental impairment?
Fragile X syndrome
Where is the fragile site in fragile X syndrome?
Xq27.3 (single gene disorder)
What group does fragile X syndrome affect the most
Males (1 in 4000) twice as many as females
- Affects people of all ages and ethnic groups
What are the features of Fragile-X phenotype?
- 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
What are the genetics that cause fragile-X syndrome?
Fragile X Mental Retardation gene 1 (FMR1)
- Trinucleotide repeat (CGG) in the 5’ non-coding region
- Expansion results in transcriptional silencing
What does the FMR1 protein do?
- 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
What abnormal conformations can triplet repeats adopt in vitro when unwound and at physiological salt levels and temperatures?
Hairpin conformation
What is genetic anticipation?
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
What is number of repeats is thought to make a mild/carrier of myotonic dystrophy?
50 - 500
What number of repeats are thought to cause congenital myotonic dystrophy?
> 1000
What numbers of repeats are thought to cause fragile X syndrome?
> 230 (60-200 in a mild/carrier)
What number of repeats are thought to cause Huntingtons?
> 40 (29-39 in a mild/carrier)
What has been done in animals to prevent the trinucleotide expansion?
Removal of DNA mismatch repair genes
WHat is RG6042?
- 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
What are the characteristics of alzheimer’s disease often seen in post-mortems?
- Plaques - outside cell
- Tangles - inside cell
What are tangles made up of?
Hyperphosphorylated tau
What are plaques made up of?
Amyloid Beta
What is significant in the pathology of Alzheimer’s which makes treatment difficult?
Many molecular changes are happening in the pre-clinical phase - a long time before symptoms
In what percentage of people is ALzheimer’s an autosomal dominant inherited disease?
~ 5%
What protein is associated with both Down’s syndrome and early-onset Alzheimer’s disease?
Amyloid Precursor Protein (present on chr21)
How can APP cause Alzheimer’s?
- 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
Mutations in what proteins can cause early onset AD?
- Presenilin 1 (70%) and 2 (~5%)
- APP (~25%)
WHat do presenilin 1 and 2 affect the activity of?
gamma-secretase enzyme complex
What is a risk factor for sporadic AD?
- ApoE
- 3 alleles that differ by just one amino acid
- Not certainty (can give a 15 fold risk)
What does ApoE do?
- Cholesterol transport
- CLears amyloid B
- Breakdown of apoE e4 might generate toxic products
How can we identify other genes which may be responsible for AD?
Comapring patients and nonpatients DNA - then look for disease specific SNPs
What other proteins are thought to be involved in AD?
- Clusterin
- PICALM
- APOE
How do neurofibrillar tangles arise?
Changes in the tau phosphorylation assembles in PHF assembly
What does tau stabilise?
Microtubules
What type of dementia has tau mutations that are not associated with plaques?
Fronto-temporal dementia
