Molecular Basis of Neurodegenerative Disorders

Question 1

Describe the molecular basis of Huntington’s Disease

Answer 1

• CAG trinucleotide repeat (codes for glutamine)
• excess glutamine results in protein misfolding (due to the excess of beta sheets)
• forms structures that form aggregates creating inclusion bodies in cells

Question 2

Describe the phenotype of Fragile X Syndrome

Answer 2

• long face, prominent forehead and jaw
• mitral valve prolapse
• mental impairment
• ADHD/autistic-like behaviour

Question 3

Describe the molecular basis of Fragile X Syndrome

Answer 3

• trinucleotide repeat in 5’ non-coding region (CGG which codes for FMR1 gene)
• expansions results in transcriptional silencing
• FMR1 is responsible for inhibiting the translation of glutamate responsive genes to regulate glutamate signalling
• transcriptional silencing leads to excess glutamate

Question 4

Why are trinucleotide repeats harmful?

Answer 4

• when DNA is unwound (in transcription, replication and repair processes), the sections of trinucleotide repeats are particularly vulnerable to hairpin conformations
  (base pairing within a single strand)
• this causes problems in replication

Question 5

Describe genetic anticipation

Answer 5

• as the number of trinucleotide repeats increases, the severity of the genetic condition increases
• with each generation of a genetic syndrome, the number of trinucleotide repeats increases which confers a more severe phenotype

Question 6

What is a potential solution in the circumstance of genetic anticipation?

Answer 6

• inhibit the Msh3 gene (mis-match repair gene)

- associated with promoting trinucleotide repeats so inhibiting it will decrease the frequency of it occuring

Question 7

What can be found in the brain in Alzheimer’s Disease?

Answer 7

• neurofibrillary tangles inside the cell made of tau (when phosphorylated, it decreases its affinity for microtubules which increases intracellular tau leading to aggregation and paired helical filaments forming)
• plaques outside the cell made of amyloid-beta peptides

Question 8

Describe PSEN1 and PSEN2 mutations in association with Alzheimer’s Disease

Answer 8

• associated with early onset Alzheimer’s disease
• forms part of gamma-secretase complex (which forms neurotoxic amyloid beta peptides when cleaves APP protein)
• mutations increase cleavage by gamma-secretase

Question 9

Describe ApoE mutations in the context of Alzheimer’s Disease

Answer 9

• associated with sporadic Alzheimer’s Disease
• certain alleles confer a higher risk (homozygous E4)
• involved in cholesterol transport of lipid rafts in the membrane (homozygous E4 not a good transporter however)
• A-beta peptide formation preferential in lipid rafts
• increased lipid rafts (due to inadequate transportation) results in increased formation of A-beta peptides
• protein is also not good at clearing the neurotoxic A-beta peptides

Question 10

What effects do prion diseases have on the brain?

Answer 10

• vacuoles forming in cytoplasm of neurons
• scarring due to increased astrocytes (reactive astrocytosis)
• deposition of prion plaques (infectious agent, no genetic material, proteinaceous and resistant to heat and disinfectant)

Question 11

How do prion diseases manifest?

Answer 11

• misfolded prion protein = neurotoxic
• will interact with normally folded prion protein causing a conformationcal change and accumulation of infectious prion
• transmissible from cell to cell
• causes neuronal death (removed by astrocytes which forms the ‘spongiform’ holes in the brain)