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MD4001 > Molecular Basis of Neurological Disorders > Flashcards

Molecular Basis of Neurological Disorders Flashcards

1
Q

Describe typical mRNA structure.

A

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
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2
Q

What is meant by a trinucleotide repeat ? Why are these significant ?

A
  • 3 nucleotides that can be repeated many times consecutively one after the other
  • Unstable Trinucleotide Repeats can result in disease, often affecting neurological system
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3
Q

Identify examples of diseases rsulting from unstable trinucleotide repeats.

A
  • Fragile X syndrome
  • Myotonic Dystrophy
  • Huntington’d disease
  • Fredreich’s Ataxia
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4
Q

State the pattern of inheritance of Huntington’s disease.

A

Autosomal dominant

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5
Q

Describe the clinical features of Huntington’s disease.

A
  • Presents in midline
  • Motor abnormalities (chorea and dystonia)
  • Behavioral and psychiatric changes
  • Gradual loss of cognition
  • Death
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6
Q

Which parts of the brain are affected by Huntington’s disease ?

A

Striatum is most severely affected

Atrophy of Caudate Nucleus and Putamen

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7
Q

Describe the genetic basis of Huntington’s disease.

A

-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

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8
Q

What is the normal function of HTT ?

A
  • Essential for normal development
  • Transport of vesicles along cytoskeleton- maybe especially mitochondria.
  • Endocytosis.
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9
Q

Identify ethical issues associated with Huntington’s disease.

A
  • 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 ?
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10
Q

Describe the main clinical features of Fragile X Syndrome.

A
  • 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
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11
Q

Describe the genetic basis of Fragile X chromosome.

A
  • Single gene disorder on X chromosome

- Fragile site is Xq27.3

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12
Q

Describe epidemiology of fragile X syndrome.

A

-Affects males and females of all ages and ethnic groups (more M than F in the 2:1 ratio)

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13
Q

Describe the genetic basis of Fragile X Syndrome.

A
  • 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
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14
Q

Why are trinucleotide repeats prone to expansion ?

A
  • 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.
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15
Q

Describe the genetic basis behind myotonic dystrophy.

A

CUG repeat in 3’UTR. Prevents RNA processing.

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16
Q

Identify the main clinical features of myotonic dystrophy.

A
  • Bilateral cataracts
  • Muscle symptoms
  • Facial weakness (including possible ptosis)
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17
Q

Explain what is meant by genetic anticipation.

A

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)

18
Q

Describe timeline of AD.

A

Can be early onset, or sporadic.

19
Q

Describe the main histological features of AD.

A
  • 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.-
20
Q

Describe timing of pathology cf clinical course in AD.

A

Change in tau protein (tangles) occurs later than plaque deposition .

21
Q

Identify a risk factor for early onset AD.

A

-Down’s syndrome (because APP gene located on ch 21)

22
Q

Describe the inheritance pattern of early onset AD.

A

Autosomal dominant

23
Q

Describe the genetic basis of early onset AD.

A
  • 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.
24
Q

What is the most common mutation in early onset AD ?

A

PSEN1 mutations, followed by PSEN2, followed by APP

25
Q

Describe the genetic basis of sporadic AD.

A
  • APOE gene (codes for APOE protein)
  • 3 alleles: eta2, eta3, and eta3 differ by single AA
  • Heterozygotes for eta4 have 3 fold increase
  • Homozygotes for eta4 have 15 fold risk
  • APOE protein normally involved in cholesterol transport + clearance of amyloid beta
  • APP is cleaved to amyloid beta in lipid rafts- cholesterol rich regions of membranes. ApoE clears cholesterol and amyloid beta. Evidence that epsilon 4 does both least well (seems to have different conformation). Therefore increased amyloid beta will both be produced, and remain in the cell.
  • Breakdown of APOE eta4 might also generate toxic products
  • ApoE eta4 may also have maximal inflammatory response to amlyoid deposition
26
Q

Define Genome wide association study.

A

Take large number of patients, pool their DNA and compare that to the DNA from ppl
that are unaffected from condition.

Look to see if any small changes in genome which are especially found at increased frequency at risk population.

27
Q

Identify genes besides APOE which are associated with Alzheimer’s disease.

A

Clusterin- binds amyloid beta, possibly involved in its clearance
PICALM- endocytosis, especially in synapses (may be involved in trafficking of amyloid beta)
CR1- promotes inflammatory response
TREM2- promotes phagocytosis of amyloid beta by microglia (causes inflammation)

28
Q

How are neurofibrillar tangles related to plaques ?

A

Phosphorylation of tau results in less affinity for microtubules, increased cytoplasmic tau, promotes aggregation and ultimately paired helical filaments form (deposited in the neuron).
This impairs axon transport.

29
Q

Does amyloid beta affect tau ?

A

Unclear, could be two independent pathways or could be related.

Some patients have Tau mutations, resulting in fronto-temporal dementia with parkinsonism (no plaques), which led some to think causative problem is Tau rather than amyloid beta

30
Q

Identify possible therapies based on the molecular basis of AD.

A
  • Secretase inhibitors (have not been working well, undermining amyloid hypothesis)
  • Preventing phosphorylation of Tau
  • Aggregation inhibitors (both Tau and amyloid beta)
  • Statins (to decrease cholesterol)
  • Immunisation
31
Q

State the other name of prion diseases. Identify the main types of it.

A

Transmissible Spongiform Encephalopathy

  • Creutzfeld-Jakob Disease
  • Fatal Familial Insomnia
  • Kuru (happens with cannibalism)
32
Q

Identify the main clinical features of prion diseases.

A

Confusion and forgetfulness progressing to cortical dementia and ataxia. Death follows.

33
Q

To what extent are prion diseases inherited ?

A

MAINLY sporadic (85%)
Inherited (10-15%)
Acquired (normally rare)

34
Q

Describe the microscopic changes occurring in prion diseases.

A
  • Vacuolation occurs within neurones cytoplasm.
  • Reactive astrocytosis – increase in astrocytes and scarring of astrocytes deposition of fibrous material
  • Deposition of prions
35
Q

What is a prion ?

A
  • Proteinaceous
  • Infectious
  • No genetic material
36
Q

Describe the genetic basis of prion diseases.

A

Normal gene which expresses a prion protein, known as PrPc. It has alpha helices, and a couple of beta pleated sheets.
Infectious agent has different conformation, increased amount of beta pleated sheets. (called PrPSc).

Not change in sequence (just different structure), so difficult for body to make immune response to it

Infection with small amount of abnormal forms, can lead to propagation through interaction
with normal form of protein (deposition of these protein with increased beta pleated sheets form fibers, which are toxic, and result in neuron death, so astrocytes invade to remove dead neuron, leaving behind characteristic spongy holes in the brain)

37
Q

To what extent are prion diseases resistant to heat and disinfectants ?

A

Resistant to heat and disinfectants

38
Q

Describe normal function of Prion protein.

A
  • Membrane protein, anchored with GPI-anchor
  • Glycosylated
  • Especially found in synaptic membranes of neurones
39
Q

Describe behaviour in mice lacking PrP protein.

A

Mice lacking PrP develop and behave normally. May have altered circadian rhythms and sleep patterns.

40
Q

What are the main ways to get prion disease ?

A

3 ways to get prion disease- direct exposure to infectious agent (eg beef burger, human growth hormone or blood products)= vCJD, genetic mutation or spontaneous

41
Q

Describe the time of onset of sporadic, vs variant CJD.

A

Variant CJD= 19-39 (and longer duration)

Sporadic= 55-70

42
Q

Identify prospects for therapy of CJD.

A
  • Stabilising PrPc conformation
  • Clearance of PrPSc
  • Vaccination against PrPSc

MD4001 (74 decks)

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