SCI regeneration

Question 1

What are the seminal experiments for extrinsic differences with CNS/PNS?

Answer 1

Tello (1910) and Aguayo (1980)

Question 2

Aguayo (1980)

Answer 2

demonstrated that at least some mature CNS neurons retain their ability to regenerate on permissive PNS grafts, whilst they cannot regenerate in their native environment.

Question 3

What are the 2 major classes of molecules that inhibit regeneration?

Answer 3

Myelin-associated inhibitors and chondroitin sulfate proteoglycans.

Question 4

Name 3 MAIs

Answer 4

• Nogo-A
• Myelin associated glycoprotein
• Oligodendrocyte myelin protein

Question 5

What do all the MAIs interact with?

Answer 5

Nogo-66 receptor

Question 6

Schwab (1990)

Answer 6

Myelin injected into mouse, Abs generated against an inhibitory factor in the myelin, so that regeneration of axons in the corticospinal tract was observed.

Question 7

What makes rodent CST not a good model for human CST?

Answer 7

CST axons lie at the base of dorsal columns and terminate in the dorsal horn. Cutting the CST means you also have to cut the dorsal columns.

Question 8

Lee (2009)

Answer 8

Nogo deletion mutant that is null for all known isoforms of Nogo. Analyses failed to reveal any enhanced CST regeneration after experimental SCI.

Question 9

What are the molecules involved in Nogo-related axon regeneration

Answer 9

Rho A and ROCK.

Question 10

Murinson (2005)

Answer 10

Selective rhizotomy in the rat showing that schwann cells of degenerating efferents incorporated 3H thymidine, whose myelinating intact sensory axons did not. Suggest diffusible mitogen induces non-myelinating SCs to enter cell cycle but axonal contact can block this response.

Question 11

What do SCs form?

Answer 11

bands of Bugner within basal laminar of the nerve- rich in laminin, encouraging axonal growth.

Question 12

Suigara (2000)

Answer 12

LIF KO mice show delayed macrophage migration into the injured nerve and delayed myelin clearance during Wallerian degeneration. LIF released from SCs.

Question 13

Vaughn and Pease (1970)

Answer 13

Early EM studies showing enucleation of the eye resulted in survival of 60-70% of OCs in quiescent state- only a small number appear to phagocytose myelin.

Question 14

Why is the CNS inaccessible to leukocytes

Answer 14

Entire length of PN becomes accessible to heamatogenous macrophages, BBB only disrupted at site of injury.

Question 15

Kim (2003)

Answer 15

substantially improved regeneration found in Nogo-A/B mouse knockout after SCI, with associated locomotor recovery.

Question 16

Critique of Kim (2003)

Answer 16

• Hard to prove regeneration and not plasticity

- Mouse model of SCI not a good model for human.

Question 17

Sorfroniew (2016)

Answer 17

Prevented astrocyte scar formation through ganciclovir inducible destruction of astrocytes- in mouse model of SCI - weight drop. Mice without astrocyte activity failed to form scars, exhibited larger areas of damage. CSPGs produced by other cells? Also showed that local delivery of hydrogel depots containing axon growth factors encouraged axon regrowth, but inhibiting scar formation reduced regrowth.

Question 18

Zhao (2013)

Answer 18

Combination treatment with anti-Nogo-A and chondroitinase ABC in rat dorsal column lesion model promoted significant recovery in a forelimb reaching task.

Question 19

Zhao (2013) critique

Answer 19

Partial lesion model not gold standard. Different makeup of the rat spinal cord, not a good model for humans.

Question 20

Why are DRG neurons good models for SCI?

Answer 20

Pseudounipolar with axons that extend in peripheral process to receptors in periphery and central process to spinal cord.

Question 21

Neumann and Woolf (1999)

Answer 21

A peripheral conditioning lesion allows regeneration of subsequently injured central branch, a process that is transcription dependent. Effects of peripheral conditioning injury can be replicated by numerous factors such as cAMP therefore crucial signal.

Question 22

Bomze (2001)

Answer 22

co-expression of GAP-43 and CAP-23, two major growth cone proteins in adult DRG neurons increases their regenerative capacity

Question 23

Franssen (2015)

Answer 23

Genetic knockdown experiments in mice with fluorescently labelled integrins demonstrated role of ARF6 in regulating reterograde trafficking of integrins away from axon. Developmental activation of gene may be responsible for lack of regenerative capacity. Overexpression of ACAP-GTPase involved in anterograde integrin trafficking shows axon growth restored.

Question 24

Mishra (2016)

Answer 24

Blocked astrocyte clacium elevations in cortical brain slices with BAPTA. Reduction in dilation of capillaries - no effect on arterioles.

Question 25

Kraft (2013)

Answer 25

Transgenic mouse line with GPAP and VIM intermediate filament proteins for astrocyte activation deleted - on model AD background (APP/PS1). Gene deletions increased the amyloid plaque load.

Question 26

Liu (2017)

Answer 26

cKO in LRP1 in astrocytes on amyloid model - therefore clear role of astrocytic LRP1 in brain Abeta clearance. ApoE also a ligand for LRP1 , therefore may compete with Abeta for cellular uptake into astrocytes.