Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination

Nat Neurosci., 2011 · DOI: 10.1038/nn.2855 · Published: August 1, 2011

Simple Explanation

White matter damage in newborns can lead to cerebral palsy and cognitive issues, while similar damage in adults contributes to multiple sclerosis (MS). The study found AXIN2 expression in immature cells in white matter lesions of newborns with brain damage and in adults with active MS lesions. Axin2 regulates remyelination, the process of repairing damaged myelin sheaths. A small molecule inhibitor, XAV939, stabilizes Axin2 levels and accelerates the differentiation and myelination of cells after injury. These findings suggest that Axin2 is an important regulator of remyelination and a potential target for drugs aimed at improving this process.

Study Duration

Not specified

Participants

Human neonatal brain tissue samples, wild type and Axin2-lacZ heterozygous mice, adult mice

Evidence Level

Level Unknown, in vitro and in vivo studies

Key Findings

1
AXIN2 mRNA marks OLP in human neonatal white matter injury
2
Axin2 function is required for OLP differentiation
3
Axin2 protein stabilization promotes OLP differentiation

Research Summary

The study investigates the role of Axin2, a Wnt signaling target, in newborn brain injury and remyelination. It finds Axin2 expression in immature oligodendrocyte progenitor cells (OLP) within white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as active MS lesions in adults. The research demonstrates that Axin2 function is essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which stabilizes Axin2 levels in OLP, accelerates their differentiation and myelination after hypoxic and demyelinating injury. The findings suggest that Axin2 is an essential regulator of remyelination and a potential pharmacological checkpoint in this process, offering a therapeutic target for conditions involving myelin damage.

Practical Implications

Therapeutic Target

Axin2 is identified as a potential therapeutic target for promoting remyelination in newborn brain injuries and multiple sclerosis.

Pharmacological Intervention

Small molecule inhibitors like XAV939, which stabilize Axin2 levels, could be used to accelerate OLP differentiation and myelination after injury.

Understanding Myelination

The study enhances the understanding of the molecular mechanisms that regulate myelination and remyelination, particularly the role of the Wnt pathway.

Study Limitations

1
Further work is needed to confirm this proposal in other human neuropathological conditions (e.g., spinal cord injury).
2
It is unclear whether the effect of dysregulated Wnt signaling is sufficient to account for stalled OLP maturation
3
Further study of systemic XAV939 (and similar agents that stabilize Axin2) administration is needed to determine possible toxicity and efficacy

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