13-10-23 - Molecular basis of some neurological disorders Flashcards
Learning outcomes
- Relate genetic changes to molecular mechanisms of some neurodegenerative diseases
- Explain the concept of genetic anticipation
- Recognise that multiple genetic traits may contribute to neurodegenerative diseases
- Discuss the molecular basis of infectious neuropathies
What is there present and the start and end of a gene?
What is their purpose?
Where can trinucleotide repeats occur?
- At the start and end of a gene, there are 5’ and 3’ untranslated sequences with start (AUG) and stop (TAA) codons next to them
- At these start sequences, ribosomes may bind, and the end sequence is to increase stability
- Trinucleotide repeats can occur throughout a gene e.g CAG
If there are too many trinucleotide repeats next to each other what can this lead to?
What trinucleotide repeat causes the following conditions:
1) Fragile X Syndrome
2) Fredreich’s Ataxia
3) Huntington’s Disease
4) Myotonic Dystrophy
- If there are too many trinucleotide repeats next to each other, this can lead to Unstable Trinucleotide Repeat Disorders in Humans
- Trinucleotide repeat causes the following conditions:
1) Fragile X Syndrome - CGG
2) Fredreich’s Ataxia - GAA
3) Huntington’s Disease - CAG
4) Myotonic Dystrophy - CTG
What type of inheritance is Huntington’s Disease (Chorea)?
At what age does it typically present?
What are 4 signs/symptoms of Huntington’s Disease (Chorea)?
How many patients present with psychiatric abnormalities and a combination of cognitive and motor disturbances?
What structures in the brain are affected?
- Huntington’s Disease (Chorea) inheritance is Autosomal Dominant (~1/25,000, although this varies by ethnic group)
- Presentation begins in midlife
- 4 signs/symptoms of Huntington’s Disease (Chorea):
1) Motor abnormalities (chorea and dystonia)
2) Behavioural and psychiatric changes
3) Gradual loss of cognition
4) Ultimately death - The striatum is the most severely affected
- There is also atrophy of the caudate nucleus and putamen
Why is Huntington’s disease (HD) also called Chorea?
- Huntington’s disease (HD) is also called Chorea as it means ‘dancing’
- This references the involuntary movements seen in Huntington’s
Where do the trinucleotide repeats that cause HD occur?
What does this trinucleotide code for?
What are 4 effects of extra glutamine residues?
- Trinucleotide repeats (CAG) that cause HD are present in the coding region
- CAG codes for glutamine, meaning there is a Polyglutamine in the coding region (exon) in HD
- 4 effects of extra glutamine residues:
1) Protein misfolds
2) Aggregates
3) Inclusion bodies
4) Impaired transport along neurons
What are 4 ethical issues surrounding HD?
- 4 ethical issues surrounding HD:
1) HD usually occurs after the reproductive years
2) There is no cure
3) Does an asymptomatic at-risk individual have a duty to undergo testing and learn the result before reproducing?
4) Is it ethical to allow asymptomatic children from families with HD to be tested?
What is Fragile X syndrome? What is it the leading cause of?
Who does it affect?
Which sex is affected more severely?
Where is the fragile site?
- Fragile X syndrome is a single gene disorder on the X chromosome
- Leading cause of inherited learning difficulties
- Affects males and females of all ages and ethnic groups - 1/4000 males, 1/8000 females
- Males tend to be affected more severely, as they only have 1 X chromosome
- The fragile site is (Xq27.3)
What are 5 features of the Fragile-X phenotype?
- 5 features of the Fragile-X phenotype:
1) Long face - prominent forehead & jaw
2) Mitral valve prolapse
3) Learning Difficulties (IQ typically around 40)
4) Attention deficit / hyperactivity disorder
5) Autistic-like behavior – tactile defensive,poor eye contact, hand-flapping
What is present on the Fragile X Mental Retardation gene 1 (FMR1)?
What is a trinucleotide repeat (TNR) expansion?
What toes TNR expansion occur in the FMR1 gene?
What effect does this have on the gene?
- Fragile X Mental Retardation gene 1 (FMR1) is an example of a trinucleotide repeat in the 5’ noncoding region
- Trinucleotide repeat (TNR) expansion occurs when the number of triplets present in a mutated gene is greater than the number found in a normal gene
- In the FMR1 gene, there is TNR expansion in the 5’ untranslated region at the start of the gene, where there are CGG (arginine) repeats
- Excessive CGG repeats results in the gene being silenced, so no protein (FMR1 protein) is produced from this gene
Where is the FMR1 protein highly expressed?
What does it regulate?
What happens in Fragile X syndrome to the glutamate producing pathway?
- The FMR1 protein is highly expressed in neurons
- It regulates mRNA translation in dendrites
- Without FMR1 protein, there is no regulation of production of proteins in the glutamate pathway, resulting in excess protein being produced
How are triplet repeats prone to expansion?
- Triplet repeats can be prone to expansion through doubling back on themselves and adopting hairpin conformations in vitro at physiological salt levels and temperatures
What is genetic anticipation?
What is it caused by?
What is a condition this occurs in?
- Genetic anticipation is a phenomenon in which the signs and symptoms of genetic conditions become more severe and/or appear at an earlier age, as they are passed from one generation to the next.
- Anticipation typically occurs with disorders that are caused by a trinucleotide repeat expansion.
- Through the generations, the repeats expand, meaning more repeats get added
- This occurs it myotonic dystrophy
What are the number of repeats for number, mild/carrier and affected in the following conditions (in picture):
1) Huntington’s Disease
2) Fragile X
3) Myotonic Dystrophy
What 3 things does the concept of genetic anticipation help clinically?
- 3 things does the concept of genetic anticipation help clinically:
1) Diagnosis
2) Genetic Counselling
3) Treatment
* Triplets expansions are normally repaired by DNA mismatch repair systems
* Expression of a particular mismatch repair protein (Msh3) resulted in greater expansion frequency
* With natural variation, it means some people will be protected more than others
* Knowing there is a chance for genetic expansion due to genetic anticipation, we can use inhibitors of this protein
* We can also develop genetic medicine for HD, where an ASO (antisense oligonucleotide) can flag HTT mrna for destruction, so the HTT protein that is part of the mechanism for the development of HD Is produced less
What are the 2 forms of Alzheimer’s disease (AD)?
Where does Alzheimer’s start in the brain and where does it progress to?
What group is particularly susceptible to early onset Alzheimer’s?
What indication does this give us?
What are 2 common post-mortem characteristics of Alzheimer’s?
What is the mechanism behind them?
- 2 forms of Alzheimer’s disease (AD):
1) Early onset
* Autosomal dominant
* Approximately 5% of all Alzheimer’s
2) Sporadic (The sudden and unpredictable occurrence of some disease or infection)
* Most Alzheimer’s disease does not run in families and is described as “sporadic”
- Alzheimer’s start in the entorhinal cortex, and spreads to the hippocampus then cerebral cortex
- Those with down syndrome are particularly susceptible to developing early-onset Alzheimer’s
- This suggests that the gene mutation responsible for the development could be on chromosome 21, which affects amyloid precursor protein (APP)
- 2 common post-mortem characteristics of Alzheimer’s:
1) Plaque
* Outside of neurons
* Amyloid beta proteins deposited
2) Tangle
* Within neurons
* Due to large amounts of hyperphosphorylated tau protein associated with microtubules
How long is the pre-clinical phase of Alzheimer’s?
- Alzheimer’s has a long pr-clinical period (15-20) years the onset of cognitive impairment and symptoms start to appear (symptomatic AD is 7-10 years
Early onset Alzheimer’s disease family tree (in picture)
Where is amyloid precursor protein (APP) normally found?
What is its role?
How is amyloid precursor protein normally handle in the body?
Describe how this is different in the development of early-onset AD
- Amyloid precursor protein (APP) is expressed and concentrated in neurons, where it regulates synapse formation – locations consistent with symptoms observed in AD
- In normal circumstances, amyloid precursor protein (APP) is cleaved by alpha-secretase
- In early-onset AD this process differs
- APP mutations increase beta-secretase activity and PSEN1/PSEN2 mutations increase gamma-secretase activity
- This results in amyloid-beta proteins being formed, which can accumulate and form an oligomer aggregate outside of the cell
- These aggregates can accumulate outside of neurons and cause loss and neuronal death
What are 2 roles of the APOE protein?
Which form of APOE is not good at either of these roles?
What can the breakdown of apoE e4 lead to?
- 2 roles of the APOE gene:
1) Cholesterol transport
2) Clears amyloid beta protein
- The e4 APOE gene is not good at either of these roles
- Breakdown of apoE e4 might generate toxic products
How can we determine if any other genes are implicated in Sporadic AD?
Describe this process.
What 3 proteins that have been implicated in Sporadic AD from genome-wide association studies?
- To determine is any other genes ae implicated in Sporadic AD, we can use a genome-wide association study
- We take a group of affected patients with symptoms, and a group of non-infection people and pool their DNA together
- We can see if single gene nucleotide polymorphisms (naturally occurring genetic variations) occur specifically in the diseased population
- This information can then be placed on a Manhattan plot (in picture), with regions associated with a particular condition appearing as a column above a threshold
- 3 proteins that have been implicated in Sporadic AD from genome-wide association studies:
1) Clusterin
2) PICALM
3) CR1
How many small genetic variations have been implicated with Sporadic AD?
- There have been many small genetic variations in a large number of genes that result in a sporadic form of AD, so it is difficult to tell if an individual is at a high risk of a disease
Describe how familial (genetic) and sporadic AD link together on a flow chart
- How familial (genetic) and sporadic AD link together on a flow chart:
- In the familial (genetic) disease, there are well known mutations, resulting in abhorrent cleavage of amyloid beta protein
- In the sporadic form of AD, other genes (more variation) will result in amyloid beta forming oligomers that can be deposited and lead to synaptic loss and neuronal death
How are tangled formed in AD?
- In AD, tangles are formed due to hyperphosphorylation of tau proteins
- This results in tau proteins becoming sequestered in tangles, which make microtubules unstable and unable to transmit signals along neurons
What are prior diseases?
What are 3 prion diseases?
What %s are inherited, sporadic, and acquired?
What are 4 common symptoms/signs of prion diseases?
- Prion diseases are transmissible spongiform encephalopathy
- 3 prion diseases:
1) Creutzfeld-Jakob Disease (CJD)
2) Fatal familial insomnia
3) Kuru - Inherited (10-15%)
- Sporadic (85%)
- Acquired (normally rare)
- 4 Common symptoms/signs of prion diseases:
1) Confusion
2) Dementia
3) Ataxia (a group of disorders that affect co-ordination, balance and speech.)
4) Death
What are prions?
Are they infectious?
Do they contain genetic material?
What are 3 ways priors can arise in our body?
- A prion is a misfolded protein that can transmit its misfoldedness to normal variants of the same protein and trigger cellular death.
- They are abnormal, pathogenic agents that are transmissible
- They are infections and contain no genetic material
- We all have potential prions in our body
- 3 ways priors can arise in our body:
1) Conversion of PrPc to mutant PrPSc
* The conformation of proteins can change, meaning the body can struggle to produce an immune response against it
* PrPc prion protein can change conformation to PrPSc prion
2) Spontaneous generation of PrPSc
3) Inoculation of PrPSc
Describe prior propagation diagram (in photo)
What effect does aggregation/deposition of prions lead to?
How does this affect neurons?
- Aggregation/deposition of prions leads to deposition of toxic fibres that can kill neurons
- They can spread and kill other cells
- Astrocytes invade to remove dead neurons, leaving behind the spongy holes seen in histology, hence ‘transmissible spongiform encephalopathy’
