Restoring Wnt6 Protein Eases Behavioral, Motor Impairment, Mouse Study Suggests

Restoring the levels of Wnt6, a signaling molecule involved in brain function, eased motor and behavioral difficulties in a mouse model of Rett syndrome, a study shows.

These findings added to scientists’ knowledge of the underlying molecular mechanisms of Rett and may help develop new therapies for those with the neurodevelopmental disorder.

The study, “Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome,” was published in the journal Scientific Reports.

Almost all cases of Rett syndrome are caused by mutations in the MECP2 gene, which contains instructions to produce the MeCP2 protein. MeCP2 regulates the activity of other genes, and is involved in nerve cells’ growth and communication.

A team from Taiwan previously reported that mice with the most common Rett-associated MECP2 mutations showed significantly reduced levels of MeCP2 SUMOylation compared with healthy mice. SUMOylation is the addition of small proteins — called small ubiquitin-like modifier (SUMO) proteins — to other proteins, regulating their function and location within the cell.

These mice also showed a nearly 12-fold reduction in the levels of Wnt6, one of 19 Wnt proteins involved in the Wnt/β-catenin signaling pathway. These proteins play a critical role during development and in adult brain function.

Reintroducing the functional MECP2 gene or restoring the levels of the SUMOylated form of MeCP2 rescued the behavioral deficits in these mice, easing the difficulties first shown.

These findings suggested that a deficient Wnt6 signaling may play a role in the development of Rett syndrome, and that restoring its activity could ease disease symptoms in a mouse model.

To test this hypothesis, the team evaluated whether restoring Wnt6 signaling could rescue the behavioral difficulties in mice with a common Rett-associated MECP2 mutation. The researchers induced an increase in Wnt6 levels specifically in the amygdala, a brain region involved in emotions and behavior.

The results showed that the restoration of Wnt6 signaling partially, but significantly, rescued not only social behavioral deficits, but also motor difficulties compared with untreated mice.

The team noted that, while the amygdala itself is not mainly involved in motor control, it is connected with brain regions that play such a role. As a result, Wnt6 signaling in the amygdala may indirectly influence motor function, the researchers said.

Further analyses revealed that Wnt6-associated benefits were linked with a complete restoration of MeCP2 SUMOylation, and with normalized — increased — levels of BDNF and IGF-1 proteins in the amygdala. BDNF and IGF-1 are involved in brain development and nerve cell function. Prior research showed that BDNF is impaired both in mouse models and people with Rett syndrome. In turn, treatment with IGF-1 was found to ease disease symptoms in a young girl with the condition.

Taken together, these findings suggested that Wnt6 may promote MeCP2 SUMOylation through an increase in BDNF and IGF-1 levels, the researchers said.

Additional tests also showed an association between environmental enrichment, restoration of MeCP2 SUMOylation, and higher levels of Wnt6, BDNF, and IGF-1. Environmental enrichment refers to the improved housing of laboratory animals — with sensory, physical, cognitive, and social engagement — so that they are more stimulated.

This is consistent with previous studies reporting that environmental enrichment improves motor coordination and motor learning in mouse models of Rett syndrome.

“These results shed light on the molecular mechanism underlying [Rett syndrome] and may lead to novel therapeutic options for [Rett] patients,” the scientists said.

The team noted, however, that future studies are required to better understand the links between these proteins, how environmental enrichment regulates them, and their role in the development of Rett syndrome.