Molecular basis of some neurological disorders Flashcards
What type of repeats can occur in a gene and how might a change in this affect someone?
Trinucleotide repeats can occur throughout a gene
Unstable Trinucleotide repeat disorders can occur in humans and gives rise to diseases like;
- Fragille X Syndrome (CGG)
- Fragile XE MR (CGG)
- Fredreich’s Ataxia (GAA)
- Myotonic dystrophy (CTG)
- Huntington’s Disease (CAG)
- Spinoobulbar muscular atrophy (CAG)
- Spinocerebellar ataxia type 1, 2, 6, 7, 8 and 12 (CAG)
What are the features of Huntington’s Disease (Chorea) ?
Huntington’s Disease (Chorea - means to dance due to dystonia/muscle spasm);
- Autosomal dominant (1/25,000 although this varies by ethnic group)
- Presentation begin in midlife - motor abnormalities (chorea and dystonia), behavioural and psychiatric changes, gradual loss of cognition and ultimately death
- 1/3rd of patients present with psychiatric abnormalities; 2/3 have a combination of cognitive and motor disturbances
- Striatum most severely affect - atrophy of caudate nucleus and putamen
What goes wrong in Huntington’s disease ?
A trinucleotide repeat in the coding region
An extra glutamine is inserted into the coding region (exon), the protein is altered and Polyglutamine expansion is made
Why is the insertion of the extra glutamine in Huntingtons residues harmful ?
It makes;
- Protein misfolds
- Aggregates within nerves
- Inclusion bodies
With expanded glutamine forms aggregates within nerves.
What are the ethical issues surrounding Huntingtons disease?
- Huntington’s disease usually occurs after the reproductive years (so passed on before knew)
- There is no cure
- Does an asymptomatic at-risk individual have a duty to undergo testing and learn result before reproducing ?
- Is it ethical to allow asymptomatic children from families with Huntington’s to be tested?
What are the features of fragile X syndrome?
Fragile X;
- Leading cause of inherited mental impairment
- Single gene disorder on X chromosome
- Affects males and females of all ages and ethnic groups
- 1/4000 males and 1/8000 females (as women have XX)
- “fragile” site (Xq27.3)
Called fragile as had this constriction here under microscope (image)
What is the phenotype of someone with Fragile X Syndrome ?
- Long face - prominent forehead and jaw
- Mitral valve prolapse
- Mental impairment (I.Q. 20-60)
- Attention deficit/hyperactivity disorder
- Autistic like behaviour - tactile defensive, poor eye contact, hand-flapping
What goes wrong in Fragile X Syndrome ?
Fragile X Mental Retardation gene 1 FMR 1
Another example of a trinucleotide repeat but in the 5’ non coding region
Expansion results in transcriptional silencing
Repeated CGG makes it harder for messenger RNA to be made so we produce less FMR1 protein
What is the function of FMR1 protein and how may it vary in Fragile X Syndrome ?
FMR1 Protein;
- Highly expressed in neurons
- Regulates mRNA translation in dendrites
Get no regulation of mRNA translation and the protein stops translation of other messenger RNA’s
Currently an antagonist or mutation for the glutamate receptor is being trialled to correct this
What are “hairpin conformations”?
Triplet repeats associated with human disease can adopt hairpin conformations in vitro at physiological salt levels and temperatures
When DNA is unwound and have certain RNA structures can form a hairpin structure on its own whereas normal stranded DNA would head out to side
Hair pin is potentially hazardous as causes expansion with repeated replication
What is genetic anticipation and a condition associated with it ?
Genetic anticipation is another trinuclotide issue. Its a phenomenon in which the signs and symptoms of some genetic conditions tend to become more severe and/or appear at an earlier age as the disorder is passed from one generation to the next.
Can see different severities of disease in these family members
Grandma has a certain number of repeats just more than the population but mother has even more and child therefore gets even more
Seen badly in Myotonic Dystrophy, also a little in Huntington’s and more in Fragile X
What are the features of Myotonic Dystrophy
A three generation family showing the grandmother who has bilateral cataracts but
no muscle symptoms or facial weakness; her daughter has moderate facial
weakness with ptosis (drooping eyelids) and cataracts; the child has the congenital
form
How can genetic anticipation help clinically?
It allows us to give;
- Diagnosis
- Genetic counselling
- Treatment ? (If applicable)
How could Genetic Medicine help Huntingtons patients?
RG6042 is an investigational molecule designed to target the underlying genetic cause of Huntingtons disease
Antisense oligonucleotide RNA’s - in order to block expression of protein causing disorder
Experimental but might be able to generate different Antisense oligonucleotides for different regions
What are the features of Alzheimers disease?
- Early onset
- Sporadic
Starts in entorhinal cortex then spreads to brain
Patients frequently have plaques outside cells with lots of amyloid beta and tangles in the cell associated with dephosphorylation of Tau
What happens in the preclinical and symptomatic years of Alzheimers ?
Decrease in synaptic/neuronal function and density just before onset of cognitive impairment and drops after
Get an increase in AB deposition (neurotic plaques), Microglia and astrocyte activation and Tau pathology in the run up to the onset of cognitive impairment and after it.
Preclinical phase is 15 - 20 years whereas disease itself is 7 - 10 years
We could maybe use these changes to predict if someone will develop Alzheimer’s and intervene to reduce or prevent ?
How can Alzheimers be passed on?
About 5% of all Alzheimers is an autosomal dominant condition
The risk of Alzheimers is high in people with Down syndrome which might mean is more present of chromosome 21 when you have 3 copies and expressed more - this is true
What mutations can occur in the proteins that cleave the amyloid precursor protein (APP)?
Mutations of the the Amyloid precursor protein (APP) will cause an increase B-secretase cleavage (Over 25 different mutations of APP)
PSEN 1/ PSEN 2 mutations increase y-secretase activity (Over 150 different mutations of PSEN 1 and 11 of PSEN2)
Both of these mutations cause more AB peptides to be produced as the abnormal pathway route is favoured which leads to excess amyloid accumulation forming aggregates outside the cells which can be seen in early onset Alzheimers disease
How does sporadic Alzheimers disease happen?
Sporadic Alzheimers disease happens due to subtle changes in the APOE gene
- 3 alleles e2, e3 and e4 differ by a single amino acids
- Heterozygotes for e4 - 3 fold risk
- Homozygotes for e4 - 15 fold risk
Not certainty
What does the APOE gene do?
- Its largely involved in cholesterol transport
- Clear amyloid B
- Breakdown of APOE e4 might generate toxic products
What additional gene mutations can influence Alzheimers disease?
Clusterin, PICALM, CR1
Give a brief summary for the causes of Familial and Sporadic Alzheimers disease and the gene causes and how it affects the cells?
Image
How are neurofibrillary tangles related to plaques ?
Tau stabilises microtubules (important in axonal transportation) but when tau is phosphorylated the microtubule defragments and Paired Helical Filaments (PHF) are formed
What do mutations in Tau cause?
Tau mutations cause Fronto-temporal dementia with Parkinsonism (no plaques)
Give a summary of how APP and Tau work?
Image
Answer to question in pic, we are unsure
A drug has been found to slow down Alzheimer’s mental decline, what is the name of the drug?
Lecanemab
Based upon our current knowledge what could we design in order to reduce the symptoms or occurrence of Alzheimers disease?
- Aggregation inhibitors (both Tau and Amyloid Beta)
- Secretase inhibitors
- Prevent phosphorylation of Tau
- Statins (APOE pathway and cholesterol metabolism)
- Immunisation against deopoisits of amyloid beta?
What are Prion diseases and the different subtypes ?
Prion diseases are transmissible spongiform encephalopathy - Starts with confusion and forgetfulness developing inot dementia and ataxia
Subtypes;
- Creutzfeld-Jakob disease
- Fatsal famllial insomnia
- Kuru (Disease particularly prevalent in Papua new guinea due to cannibalism lifestyle)
- 10 - 15% inherited
- 85% Sporadic
- Acquired (normally rare)
What would the brain of someone with Prion disease look like ?
“Spongiform Brain”
Image
What is a Prion?
Infectious agent just containing only protein no DNA. Very resistant to heat or disinfectant.
- Proteinaceous
- Infectious
- Not genetic material
- Acquired through infectious agent
How does Prion work?
Has a unique conformation that is thought to be able to alter similar proteins - e.g PRP gene swaps alpha helix to pleated sheet - infectious (image)
Something triggers the conversion of a single prion protein (PRP) to a mutant conformation and it then somehow converts the normal conformation into this strange conformation
This is then spread from neuron to neuron and we have deposition of these amyloid like fibres which kill the neuron and the astrocytes invade to remove the dead neurones and weave behind spongy holes hence what we see
What is the normal function of the Prion precursor protein (PRPN)
- GPI - anchor
- Glycosylated
- Synaptic membranes of neurons
- Mice lacking PrP develop and behave normally. May have altered circadian rhythms and sleep patterns
What happened in Bovine Spongy Encephalopathy in 1990’s?
In 1990’s cow versions bovine spongy encephalopathy. Found that half a million of cows had it and worries about it getting into food chain, changes in public health on parts of animals you can eat etc
How does the an acquired Prion (Variant CJD) differ from a sporadic one and how did this worry people in 1990’s?
Acquired Prion (Variant CJD) has a much longer incubation period.
This caused concerns for pre-clinical transmission, caused changes in regulations for giving blood, gave worries donor was in pre-clinical phase of disease and pass on disease to someone else, ban if you were a blood recipient within a certain time period - 4 instances of people getting this disease from contaminated blood
