Axon Regeneration

Question 1

What are the goals of restorative neuroscience?

Answer 1

Inhibit formation of the glial scar, inhibit inhibitory signalling that prevents axon regeneration, promote pro-regenerative pathways, replace lost cells, and promote functional reconnectivity

Question 2

In nerve injury, membrane disruption leads to an influx of which two ions?

Answer 2

Calcium and sodium

Question 3

How does the ion influx after membrane disruption help axon regeneration?

Answer 3

It leads to disinhibition of some gene transcription, and activation of some gene transcription - some of which are genes involved in growth

Question 4

How does local translation at the growth cone after PNS injury affect actin?

Answer 4

It leads to ubiquitination, which is important for actin polymerisation

Question 5

How is chromatin involved in axon regeneration after PNS injury?

Answer 5

Before injury, chromatin is highly methylated and deacetylated, so not very accessible to transcription factors. Injury leads to acetylation, making it more accessible to activated transcription factors and driving axonal outgrowth. This does not occur in the CNS, and is one of the main barrier to CNS regeneration

Question 6

How do chrondroitin sulphate proteoglycans (CSPGs) inhibit axon regeneration in the CNS?

Answer 6

They are produced by astrocytes and bind to Nogo receptors and p43-gamma. These tyrosine kinase receptors activate the conversion of Rho A to ROCK, inducing growth cone collapse

Question 7

What is No-go?

Answer 7

A myelin protein found in the extracellular space following nerve injury due to the disruption of myelin and oligodendrocytes

Question 8

What are the functions of mTOR?

Answer 8

Activating translation and protein synthesis

Question 9

How does deleting PTEN promote spinal cord regeneration after injury?

Answer 9

It activates PI3kinase, which activates mTORC2, promoting protein synthesis and regenerative signalling

Question 10

What is the rubrospinal tract?

Answer 10

The rubrospinal tract originates from the red nucleus in the midbrain and is very important for locomotion

Question 11

PCAF overexpression in rodents promotes spinal cord regeneration. Why was this molecule chosen as a target?

Answer 11

PCAF is activated by phosphorylation following lesions that later regenerate, but not by lesions that do not regenerate

Question 12

Different areas of the CNS are thought to have different capacities for regeneration. In which part is capacity thought to be highest?

Answer 12

Dorsal columns and dorsal root ganglia

Question 13

Which part of the spinal cord is thought to have the lowest regenerative capacity?

Answer 13

Corticospinal tract

Question 14

What is the raphespinal tract?

Answer 14

A 5-HT (serotoninergic) tract which originates in the mesencephalon and carries motor fibres

Question 15

What factors influence the ability of a neuron to regenerate?

Answer 15

The innate properties, the type of lesion, and its distance from the cell body

Question 16

What is the prevalence of spinal cord injury in the UK?

Answer 16

50,000

Question 17

State the 3 main causes of neurological impairment in spinal cord injury

Answer 17

1) Poor intrinsic neuronal regenerative capacity
2) Presence of a growth inhibitory environment
3) Cell loss and the imperfect generation of new cells

Question 18

Which cells accumulate first after spinal cord injury?

Answer 18

Microglia

Question 19

Name 3 compounds deposited to form the glial scar

Answer 19

Fibronectin, collagen, tenascin

Question 20

Why is the NogoA antibody proposed as an intervention in spinal cord injury?

Answer 20

It blocks the inhibition of axon growth by Nogo

Question 21

Why is chondroitinase proposed as an intervention in spinal cord injury?

Answer 21

It digests chondroitinase sulphate proteoglycans (CSPGs) to reduce the glial scar

Question 22

Why are cyclic AMP analogues proposed as an intervention in spinal cord injury?

Answer 22

They stimulate growth cone remodelling

Question 23

Why are phosphodiesterase inhibitors proposed as an intervention in spinal cord injury?

Answer 23

They increase the amount of cyclic AMP, enhancing intrinsic regenerative ability of axons

Question 24

Why is taxol proposed as an intervention in spinal cord injury?

Answer 24

It promotes intrinsic regeneration and blocks extrinsic inhibition

Question 25

Why are Rho GTPases proposed as an intervention in spinal cord injury?

Answer 25

They can overcome Mag-Nogo inhibition of regeneration

Question 26

What is taxol?

Answer 26

A microtubule stabilising agent. It is currently used in cancer

Question 27

Why are neurons not affected by taxol’s cell division blocking effects?

Answer 27

They are post-mitotic cells

Question 28

Describe the results of Lu et al (Cell, 2012)’s experiments transplanting embryonic stem cells into rats with transecting spinal cord lesions

Answer 28

Long-dense fibres developed in both the grey and white matter, with some synaptic formation between themselves and surviving neurons and a significant improvement in motor function

Question 29

Describe the results of Liu et al (Nat Neurosci, 2010)’s experiments into PTEN deletion for spinal cord injury in mice

Answer 29

PTEN deletion enhanced axonal regeneration, which was associated with some improvement in the specific motor task of grasping a pellet - with greater improvement in younger animals than adult or elderly ones

Question 30

Describe the results of Wang et al (J Neurosci, 2015)’s experiments into overexpression of Sox11 for spinal cord injury

Answer 30

Overexpression of Sox11 reduced the net retraction of dorsal root ganglion neurons - with a greater impact on the corticospinal tract than sensory axons, suggesting that different molecules have different impacts on different types of neurons

Question 31

How does HDAC3 inhibit spinal cord regeneration?

Answer 31

It acetylates chromatin

Question 32

State 5 factors to consider with gene therapy

Answer 32

Route of administration, duration of effect, level of expression, toxicity, inflammatory reaction, infectivity, transgene stability, specificity to populations, and regulatory issues