Wnt/β-catenin in Multiple Sclerosis: A Nuanced Approach to Remyelination

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that affects approximately 2.8 million people worldwide, with an average onset at age 32, making it one of the leading causes of non-traumatic neurological disability in young adults.¹ Woman are disproportionally diagnosed with MS, with about twice as many women (63%) affected compared to men (31%) globally.¹ Clinically, MS manifests as relapsing–remitting and progressive disease courses, and presents with a wide spectrum of neurological deficits including optic neuritis, sensory disturbances, motor weakness, cerebellar and brainstem dysfunction, urinary impairment, and ataxia.^2,3 Although inflammation is most prominent early in the disease, cumulative disability correlates more closely with axonal loss and failure of repair mechanisms than with relapse frequency alone.⁴

Presently the standard of care utilizes disease-modifying therapies (DMTs) which have improved the management of MS by targeting immune dysregulation and neuroinflammation.³ These agents primarily function by suppressing adaptive immune responses, limiting leukocyte trafficking into the CNS, and reducing acute inflammatory damage.^2,3 While effective at decreasing relapse rates, current DMTs do not directly promote remyelination or restore blood-brain barrier (BBB) integrity.³ As a result, many patients continue to progressively decline despite adequate control of neuroinflammation with DMTs.³ This therapeutic gap has shifted attention toward remyelination as a potential treatment to address the progressive decline seen in MS.

Remyelination is mediated by oligodendrocyte precursor cells (OPCs), which are recruited to demyelinated lesions and must then differentiate into mature myelinating oligodendrocytes (OLs). Successful remyelination restores saltatory conduction and improves functional recovery, and protects axons from degeneration.⁵ Importantly, pathological studies of MS lesions demonstrate that remyelination can occur, particularly in early or active lesions, and that patients with more remyelination exhibit lower levels of disability.⁶ However, in chronic MS lesions, OPCs persist in an undifferentiated state, indicating that remyelination failure is not due to depletion of OPCs but rather to some inhibitory signaling within the microenvironment.^5,7,8 These observations suggest that therapeutically targeting pathways that regulate OPC differentiation may represent a novel strategy towards remyelination.

The canonical wingless-related integration site (Wnt)/β-catenin signaling pathway is a highly conserved intracellular signaling cascade (Figure 1) that primarily regulates cell fate and proliferation especially in the context of oligdendroglial lineage progression and remyelination. Fancy and colleagues established the link between the Wnt signaling pathway and OPC differentiation by observing transcription factor 7-like 2 (Tcf7l2, also known as Tcf4) in toxin-induced demyelination mouse models.⁷ They found that normal adult white matter had minimal to no Tcf4 transcripts but re-expression of Tcf4 mRNA was found in demyelinated lesions during remyelination.⁷ This reactivation coincided with active β-catenin signaling and genetic activation resulted in a profound delay in differentiation without impairing recruitment to lesions, identifying differentiation as the bottleneck.⁷ These findings were mirrored in human MS tissue, where Tcf7l2-positive OLs were found in active lesions but not in chronic lesions, linking Wnt pathway activation to remyelination failure in vivo.⁷

Subsequent preclinical studies also looked into intracellular regulators of the Wnt/β-catenin signaling pathway as potential therapeutic targets such as Axin2, a scaffold protein that promotes β-catenin degradation.⁹ Although Axin2 transcription is induced by Wnt signaling, its protein stability is regulated by tankyrase mediated poly(ADP-ribosyl)ation (also described as PARsylation), which targets Axin2 for ubiquitin-dependent degradation.⁹ In demyelinated lesions, Axin2 transcripts persist in OPCs that fail to differentiate, while tankyrase activity limits Axin2 protein accumulation, permitting continued Wnt signaling. Pharmacologic inhibition of tankyrases with compounds such as XAV939 stabilizes Axin2, enhances β-catenin degradation, and improves remyelination in wild-type mice, but not in Axin2-null mice.⁹

The complexity of Wnt signaling in MS is further illustrated by its effects on different cell types. Lengfeld and colleagues demonstrated that selective inhibition in endothelial cells (ECs) worsened clinical outcomes and that Wnt/β-catenin signaling had partially protective effects on the BBB during experimental autoimmune encephalomyelitis (EAE).¹⁰ To test this, the study utilized doubly transgenic (dTg) mice that overexpressed Axin and a fluorescent protein regulated through doxycycline and then induced EAE.¹⁰ They verified selective inhibition of ECs by measuring Apcdd1 mRNA levels, a target gene and indicator of Wnt signaling activity, and found dTg mice to exhibit similar levels to wild-type mice indicating successful selective Wnt signaling inhibition in ECs.¹⁰ When clinical outcomes were compared to single-transgenic mice with EAE, the dTg mice had a higher proportion of EAE scores >1 (55% vs 30%) and a higher mortality rate (25% vs 5%).¹⁰ Wnt/β-catenin signaling in ECs also did not preserve tight or adherens junction degradation during peak EAE but instead limited leukocyte trafficking across the BBB by suppressing endothelial adhesion molecule expression and calveolar transport; inhibiting Wnt signaling in ECs during EAE removes this protective mechanism and worsened clinical outcomes.¹⁰ These findings were further supported when researchers found that teriflunomide upregulated claudin-1, a tight junction protein that promotes BBB integrity, via activation of Wnt-2b through RNA sequencing.¹¹

Wnt signaling may also be influenced by the extracellular lesion microenvironment. Extracellular sulfatases (Sulf1 and Sulf2) were identified as regulators of inhibitory signaling following demyelination.⁸ Sulf1/2 expression was elevated in MS lesions and impaired OPC recruitment and differentiation by potentiating Wnt and bone morphogenic protein (BMP) signaling.⁸ Sulfatase ablation attenuated these pathways, increased OL density and enhanced remyelination despite ongoing Wnt activation.⁸ However, combining sulfatase inhibition with a Wnt antagonist (XAV939) did not produce additive benefits, suggesting that Wnt and BMP pathways converge on a shared pathway.⁸

Research has also reevaluated the role of Tcf7l2, a Wnt effector traditionally assumed to be an inhibitor of OL differentiation. Since Tcf7l2 is primarily found in remyelinating tissues but not in chronic inactive lesions⁷, Tcf7l2 is a Wnt effector of interest in the context of remyelination. Using genetic models, Zhang and colleagues showed that Tcf7l2 promotes OL differentiation by repression of BMP4 signaling, an inhibitor of myelination.¹² With genetic models, the researchers found that deletion of Tcf7l2 upregulated BMP4 signaling by measuring an increase in Bmp4 mRNA.¹² However in the case of overexpression of Tcf7l2, OLs showed a reduced amount of BMP4 protein.¹² With simultaneous deletion of Tcf7l2 and BMP4, the defects in myelin gene expression were resolved when compared to single deletion of Tcf7l2.¹²These findings suggest that Tcf7l2 promotes OL differentiation by suppressing BMP4 signaling and adds another layer of complexity to targeting the Wnt/β-catenin signaling pathway.

The pursuit of novel pathways and interventions to address the remitting nature of MS is a new step in the right direction albeit a complicated one. The Wnt/β-catenin signaling pathway opens up new possibilities for therapeutic targets to address the need for remyelination in MS. However, interventions in the Wnt/β-catenin signaling pathway requires a nuanced approach that is aware of different Wnt components, cell-specificity, and its effects on other pathways.

Figure 1: In the absence of Wnt ligands (Wnt-OFF), cytoplasmic β-catenin is phosphorylated by a destruction complex composed of glycogen synthase kinase-3β (GSK3β), casein kinase 1 (CK1a), axis inhibition protein (AXIN), and adenomatous polyposis coli (APC), leading to its ubiquitination and proteasomal degradation resulting in transcriptional repression of Wnt target genes.¹³ During the Wnt-ON state, Wnt binds to Frizzled (Fz) receptor and lipoprotein-related protein 5/6 (LRP5/6), Dishevelled (Dsh) is activated and leads to the disassembly of the destruction complex and stabilizes and increases cytoplasmic β-catenin.¹³ The increased β-catenin then translocates intracellularly to the nucleus and binds to T cell factor/lymphoid enhancer-binding factor (TCF/LEF) and controls expression of target genes. ¹³

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