Topic06 - Brain and Related Diseases

Question 1

Discuss the epigenetic changes in relation to traumatic brain injury

Answer 1

1. Brain injury results in membrane depolarisation, resulting in calcium influx into neurons.
2. This results in the increase in calcium-dependent phosphorylation. This has two effects:
   2a. reduced CpG methylation, resulting in the errant expression of BDNF (brain development neurotrophic factor)
   2b. activation of DAXX (death associated protein), which loads H3.3 at regulatory regions of selected genes, marking active transcription.

Question 2

Briefly state the overall effect of calcium influx in neurons

Answer 2

Death

Question 3

Give an example of an miRNA that can be used as a prognostic marker to differentiate mild and severe traumatic brain injury

Answer 3

miR-16. Its expression is increased in mild TBI and decreased in severe TBI.

Question 4

Discuss the epigenetic changes in relation to (i) ischemic stroke or (ii) seizures

Answer 4

Both conditions result in REST-dependent epigenetic remodeling of the gria2 promoter.
The difference between the two pathways lie in the fact H3K914ac is downregulated in ischemia while H4ac is downregulated in seizures.
Regardless, both pathways result in the increased expression of GluA2-lacking AMPARs, which causes increased Ca2+ influx.

Question 5

Discuss the epigenetic changes in relation to focal epilepsy and febrile seizures.

Answer 5

Increased CPA6 (carboxypeptidase 6) promoter methylation

Question 6

Epigenetic modifications are always similar in a disease, even if the cause of the disease is different. TRUE or FALSE?

Answer 6

FALSE.

Question 7

The epigenome is influenced by early life experiences such as stress and neglect. TRUE or FALSE?

Answer 7

TRUE

Question 8

Define synaptogenesis

Answer 8

Synaptogenesis refers to the formation of synapses in the brain.

Question 9

Define long-term potentiation (LTP)

Answer 9

LTP is a long-lasting increase in the efficacy of communication between two neurons that results from stimulating them simultaneously.

Question 10

Define long-term depression (LTD)

Answer 10

LTD is the selective weakening of specific sets of synapses

Question 11

What is EPSP?

Answer 11

Excitatory postsynaptic potential size. EPSP increases with LTP and decreases with LTD

Question 12

What is sodium butyrate?

Answer 12

An inhibitor of HDAC

Question 13

State the effect of HDAC and HAT on LTP

Answer 13

HDAC decreases LTP and synapse formation. Conversely, HAT increases LTP, memory, and synapse formation.

Question 14

List the DNA methyltransferases expressed in adult CNS

Answer 14

DNMT1, DNMT3a/b

Question 15

What is 5-azadeoxycytidine?

Answer 15

A DNMT inhibitor.

Question 16

Define the term vehicle (in behavioural neuroscience)

Answer 16

A control substance injected into the animal

Question 17

Define the term tetanus

Answer 17

A brief train of spikes of electric shock that causes enduring, measurable enhancement of EPSP

Question 18

State the effects of double KO of DMNT1 and DNMT3a in mice

Answer 18

1. No apparent effect on brain structures nor behavioural defects observed
2. Enhanced induction of LTD and attenuated LTP
3. Decreased learning ability

Question 19

Discuss epigenetic changes in relation to fear-based learning

Answer 19

Fear learning increases H3K4me3 in specific gene promoter regions (Zif268 and BDNF) with altered DNA methylation and MeCP2 DNA binding.

Question 20

Briefly describe the pathogenesis of Alzheimer’s disease

Answer 20

1. Tau proteins are found in normal, healthy neurons. Plaque formation may occur but cellular homeostasis usually clears the plaques formed.
2. If cellular homeostasis is unable to cope with plaque formation, then Tau proteins aggregate to form an amyloid plaque.
3. Plaque formation is associated with cellular neuron death
4. Neuron death in turn leads to shrinkage of the brain, as observed in Alzheimer’s patients

Question 21

State two epigenetic marks that are implicated in Alzheimer’s disease.

Answer 21

1. Hypomethylation of BRCA1 promoter CpG (early stage Alzheimer’s)
2. Reduction of histone acetylation

Question 22

What is Trichostatin A (TSA)?

Answer 22

A HDAC inhibitor

Question 23

State the effect of TSA treatment on APP/PS1 mice

Answer 23

Wild-type phenotype is rescued in APP/PS1 mice

Question 24

Briefly describe the pathogenesis of Parkinson’s disease

Answer 24

1. Parkinson’s disease is characterised by the degeneration of dopaminergic neurons.
2. The loss of dopamine results in akinesia, rigidity and bradykinesia.
3. The loss of melanin containing neurons produce characteristic changes in depigmentation
4. The formation of Lewy bodies (abnormal aggregations of protein that develop inside nerve cells)

Question 25

Briefly describe the role of Snca

Answer 25

Snca encodes α-Syn, a protein essential for dopaminergic neurons. However, the overexpression of α-Syn is pathological.

Question 26

Briefly describe the epigenetic changes related to Snca

Answer 26

1. DNMT normally methylates CpG islands of the Snca locus. Hypomethylation (pathology) causes an increase in α-Syn production, which in turn sequesters DNMT in the cytosol (positive feedback)
2. Histone acetylation causes the increase in α-Syn expression. α-Syn in turn inhibits the expression of HATs (negative feedback)

Question 27

Briefly discuss epigenetic changes in relation to Huntington’s disease.

Answer 27

Increased methylation of promoter regions of specific genes.

Question 28

State the two possible outcomes of axonal injury, in relation to axonal fate.

Answer 28

1. If central lesion occurs, the axon will die

2. If peripheral lesion occurs, axonal regeneration will occur.

Question 29

Briefly discuss the pathways activated due to axonal peripheral lesion

Answer 29

1. Lesion causes calcium influx, which activates a variety of pathways
2. PKC is phosphorylated, causing the nuclear export of HDAC5
3. PERK-mediated histone acetylation causes the activation of genes associated with repair and regeneration
4. These epigenetic modifications increase the expression of genes involved in regeneration (RAG)

Question 30

Briefly discuss the pathways activated due to axonal central lesion

Answer 30

HDACs and DNMTs are recruited, decreasing RAG expression