Molecular Basis of Neurological Disorders Flashcards
Describe typical mRNA structure.
Structure of mRNA is the following:
- 5’ untranslated region, preceding START codon
- START codon
- Exon (coding info), possibly interrupted by intronic info (which is normally removed by splicing)
- STOP codon
- 3’ untranslated region
What is meant by a trinucleotide repeat ? Why are these significant ?
- 3 nucleotides that can be repeated many times consecutively one after the other
- Unstable Trinucleotide Repeats can result in disease, often affecting neurological system
Identify examples of diseases rsulting from unstable trinucleotide repeats.
- Fragile X syndrome
- Myotonic Dystrophy
- Huntington’d disease
- Fredreich’s Ataxia
State the pattern of inheritance of Huntington’s disease.
Autosomal dominant
Describe the clinical features of Huntington’s disease.
- Presents in midline
- Motor abnormalities (chorea and dystonia)
- Behavioral and psychiatric changes
- Gradual loss of cognition
- Death
Which parts of the brain are affected by Huntington’s disease ?
Striatum is most severely affected
Atrophy of Caudate Nucleus and Putamen
Describe the genetic basis of Huntington’s disease.
-Trinucleotide repeat (CAG- Glutamine) in the coding region (exon)
-Resulting protein has increased glutamine resides
-Residues cause protein to
misfold (due to increased H-bonding), and therefore aggregate (in the cytoplasm), especially as intranuclear inclusion bodies and cytoplasmic inclusion bodies in the motor cortex of Huntington’s disease brain
What is the normal function of HTT ?
- Essential for normal development
- Transport of vesicles along cytoskeleton- maybe especially mitochondria.
- Endocytosis.
Identify ethical issues associated with Huntington’s disease.
- HD usually occurs after the repro years
- There is no cure
- 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 ?
Describe the main clinical features of Fragile X Syndrome.
- Mental impairment (IQ 20-60)
- Long face (prominent forehead and jaw)
- Mitral valve prolapse
- Attention deficit/hyperactivity disorder
- Autistic like behavior- tactile, defensive, poor eye contact, hand flapping
Describe the genetic basis of Fragile X chromosome.
- Single gene disorder on X chromosome
- Fragile site is Xq27.3
Describe epidemiology of fragile X syndrome.
-Affects males and females of all ages and ethnic groups (more M than F in the 2:1 ratio)
Describe the genetic basis of Fragile X Syndrome.
- Trinucleotide repeat in the 5’ non coding region
- Expansion results in transcriptional silencing (promoter does not work very well, less transcript produced, less protein produced)
- FMR1 protein is highly expressed in neurons, it is a translation repressor in dendrites, so acts in opposition to mGluR.
- If decreased protein, then unchecked activation of glutamate receptor
Why are trinucleotide repeats prone to expansion ?
- Triplet repeats associated with human disease can adopt hairpin conformation in vitro
- DNA is unwound in transcription, DNA repair, replication and recombination. Thus trinucleotide repeats very vulnerable in all these processes. In some instances changes in repeat number can be dynamic between tissues, or cells of the same tissue.
- Expansion can occur in meiosis – recombination may also play a role and explain why tendency for expansion between generations if already slightly expanded and therefore unstable.
Describe the genetic basis behind myotonic dystrophy.
CUG repeat in 3’UTR. Prevents RNA processing.
Identify the main clinical features of myotonic dystrophy.
- Bilateral cataracts
- Muscle symptoms
- Facial weakness (including possible ptosis)
Explain what is meant by genetic anticipation.
The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next ( as number of repeats increases)
Describe timeline of AD.
Can be early onset, or sporadic.
Describe the main histological features of AD.
- Tangle inside cell= hyper-phosphorylated tau
- Plaque outside cell= amyloid beta (plaques most pronounced in amygdala, hippocampus and cerebral cortex. Initiates in entorhinal cortex near hippocampus.-
Describe timing of pathology cf clinical course in AD.
Change in tau protein (tangles) occurs later than plaque deposition .
Identify a risk factor for early onset AD.
-Down’s syndrome (because APP gene located on ch 21)
Describe the inheritance pattern of early onset AD.
Autosomal dominant
Describe the genetic basis of early onset AD.
- Amyloid precursor protein (APP) is a transmembrane protein that can undergo a series of proteolytic cleavage by secretase enzymes.
- When it is cleaved by α-secretase in the middle of the β- amyloid domain (Aβ), it is not amyloidogenic.
- However, when APP is cleaved by β- and γ-secretase enzymes, neurotoxic Aβ peptides are released, which can accumulate into oligomer aggregate.
- Mutations in the APP gene tend to inhibit cleavage by α-secretase and consequently enable preferential cleavage by β-secretase.
- Mutations in the presenilin- 1 and presenilin-2 genes (PSEN1 and PSEN2), which are components of the γ-secretase complex, increase cleavage by γ-secretase at this site.
- In both situations, the result is excess Aβ peptide production. The current Aβ hypothesis suggests that the soluble oligomers can impair synaptic function between neurons. Simultaneously, the oligomers may aggregate into insoluble β-sheet amyloid fibrils, which can trigger a local inflammatory response. Over time, this ultimately leads to neuronal death and the development of neuritic plaques typical of Alzheimer disease.
What is the most common mutation in early onset AD ?
PSEN1 mutations, followed by PSEN2, followed by APP
