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Unravelling the Road to Recovery: Mechanisms of Wnt Signalling in Spinal Cord Injury

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Abstract

Spinal cord injury (SCI) is a complex neurodegenerative pathology that consistently harbours a poor prognostic outcome. At present, there are few therapeutic strategies that can halt neuronal cell death and facilitate functional motor recovery. However, recent studies have highlighted the Wnt pathway as a key promoter of axon regeneration following central nervous system (CNS) injuries. Emerging evidence also suggests that the temporal dysregulation of Wnt may drive cell death post-SCI. A major challenge in SCI treatment resides in developing therapeutics that can effectively target inflammation and facilitate glial scar repair. Before Wnt signalling is exploited for SCI therapy, further research is needed to clarify the implications of Wnt on neuroinflammation during chronic stages of injury. In this review, an attempt is made to dissect the impact of canonical and non-canonical Wnt pathways in relation to individual aspects of glial and fibrotic scar formation. Furthermore, it is also highlighted how modulating Wnt activity at chronic time points may aid in limiting lesion expansion and promoting axonal repair.

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Abbreviations

Akt:

Protein kinase B

ALS:

Amyotrophic lateral sclerosis

APC:

Adenomatous polyposis coli

BBB:

Blood–brain barrier

BBB score:

Basso, Beattie, and Bresnahan score

BDNF:

Brain-derived neurotrophic factor

BMSC:

Bone marrow–derived mesenchymal stem cells

BSCB:

Blood–spinal cord barrier

CAMKII:

Calcium/calmodulin-dependent protein kinase II

CK1γ:

Casein kinase 1 gamma

CNS:

Central nervous system

CRD:

Cysteine-rich domain

CS-GAG:

Chondroitin sulphate glycosaminoglycan

CSPG:

Chondroitin sulphate proteoglycan

CST:

Corticospinal tract

DAMP:

Damage-associated molecular pattern

Dkk1/3:

Dickkopf-1/3

Dpi:

Days post-injury

Dvl:

Dishevelled

ECM:

Extracellular matrix

ERK1/2:

Extracellular signal–regulated kinase 1/2

Fzd:

Frizzled

GDNF:

Glial cell–derived neurotrophic factor

GFAP:

Glial fibrillary acidic protein

GFP:

Green fluorescent protein

GLUT-1:

Glucose transporter 1

GSK3β:

Glycogen synthase kinase 3 beta

ICKO:

Inducible conditional knockout

IHC:

Immunohistochemistry

IWR-1:

Inhibitor of Wnt response 1

JNK:

C-Jun N-terminal kinase

JUN:

Transcription factor AP-1

LAR:

Leukocyte common antigen-related receptor

LEF:

Lymphoid enhancer-binding factor

LPS:

Lipopolysaccharide

LRP5/6:

Low-density lipoprotein receptor–related protein 5/6

Lv:

Lentivirus

MAG:

Myelin-associated glycoprotein

MAPK:

Mitogen-activated protein kinase

MBP:

Myelin basic protein

MDM:

Monocyte-derived macrophage

MRI:

Magnetic resonance imaging

MS:

Multiple sclerosis

MSC:

Mesenchymal stem cells

mTOR:

Mammalian target of rapamycin

NeuN:

Neuronal nuclei

NFAT:

Nuclear factor of activated T cells

NF-α1:

Nuclear factor alpha 1

NF-κB:

Nuclear factor kappa B

NG2:

Neural/glial antigen 2

NgR1/3:

Nogo receptor 1/3

Nogo-A:

Nogo-A protein

Nrf2:

Nuclear factor erythroid 2–related factor 2

NSC:

Neural stem cells

NTR:

Netrin domain

OLP:

Oligodendrocyte lineage progenitors

OMgp:

Oligodendrocyte myelin glycoprotein

OPC:

Oligodendrocyte precursor cell

PC12:

Pheochromocytoma cell line 12

PCP:

Planar cell polarity

PDGFRα:

Platelet-derived growth factor receptor alpha

PDGFRβ:

Platelet-derived growth factor receptor beta

PI3K:

Phosphoinositide 3-kinase

PK2:

Protein kinase 2

PKC:

Protein kinase C

Rac1:

Ras-related C3 botulinum toxin substrate 1

ROCK:

Rho-associated protein kinase

Ror1/2:

Receptor tyrosine kinase-like orphan receptor 1/2

ROS:

Reactive oxygen species

Rspo1:

R-spondin 1

rt-qPCR:

Real-time quantitative polymerase chain reaction

Ryk:

Receptor-like tyrosine kinase

SCE:

Spinal cord extract

SCI:

Spinal cord injury

SFRP2/4:

Secreted frizzled-related proteins 2/4

SIRT1:

Sirtuin 1

STAT3:

Signal transducer and activator of transcription 3

TCF:

T cell factor

TGF:

Transforming growth factor

TGFβ:

Transforming growth factor beta

tMCAO:

Transient middle cerebral artery occlusion

TNF-α:

Tumour necrosis factor alpha

Wif1:

Wnt inhibitory factor 1

Wnt:

Wingless-related integration site

ZO-1:

Zonula occludens-1

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Acknowledgements

We acknowledge the Chancellor Summer Research Fellowship from Sri Ramachandra Institute of Higher Education and Research provided to Suchita Ganesan.

Funding

This work is supported by funding of AO Spine Start up grant [2021–031 Ganesan] from the AO Spine Foundation to Dr. G Sudhir, Dr. Lakshmi R. Perumalsamy, and Dr. Arun Dharmarajan.

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  1. Arun Dharmarajan

    Present address: Sri Ramachandra Faculty of Clinical Research, Sri Ramachandra Institute of Higher Education and Research, Chennai, India

Authors and Affiliations

  1. Department of Biomedical Sciences, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India

    Suchita Ganesan, Arun Dharmarajan & Lakshmi R. Perumalsamy

  2. Department of Orthopedics and Spine Surgery, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra Institute of Higher Education and Research, Chennai, India

    G Sudhir

  3. Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA, 6102, Australia

    Arun Dharmarajan

  4. Curtin Medical School, Curtin University, Perth, WA, Australia

    Arun Dharmarajan

  5. School of Human Sciences, The University of Western Australia, Nedlands, WA, Australia

    Arun Dharmarajan

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Contributions

SG: conceptualization, investigation, writing –original draft preparation, visualisation. AD: writing – review and editing. GS: conceptualization, writing – review and editing. LRP: conceptualization, writing – review and editing, supervision, project administration.

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Correspondence to G Sudhir or Lakshmi R. Perumalsamy.

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Ganesan, S., Dharmarajan, A., Sudhir, G. et al. Unravelling the Road to Recovery: Mechanisms of Wnt Signalling in Spinal Cord Injury. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04055-1

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