New possible treatment pathway for Shank3-related autism discovered

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by differences in communication, behavior and the processing of sensory information. Past research has shown that some individuals diagnosed with ASD exhibit specific genetic variants or differences in the regulation of genes.

In some patients, the Shank3 gene was found to be mutated, partially or fully deleted, or not expressed as much. This gene is known to support the creation of junctions at which connected neurons communicate with each other, known as synapses.

Past findings suggest that people diagnosed with ASD who exhibit variants in Shank3 also present abnormalities in the volume, structure and function of white matter. White matter is a brain region filled with a fatty substance known as myelin, which insulates nerves and allows signals to travel faster within the nervous system.

Myelin is produced by glial cells known as oligodendrocytes, which develop from so-called oligodendrocyte precursor cells (OPCs). When the development and maturation of these cells is impaired, this can result in the production of too little myelin (i.e., hypomyelination) and disruptions in communication between cells.

Researchers at Ulm University, Neuroscience Center Ulm (NCU) and the German Center for Neurodegenerative Diseases (DZNE) recently carried out a study aimed at further exploring how the Shank3-related genetic differences observed in some individuals with ASD influence the maturation of oligodendrocytes. Their findings, published in Molecular Psychiatry, led to the discovery of a molecular communication pathway that is influenced by the Shank3 gene, which controls the growth and maturation of cells.

“White matter abnormalities are consistently observed in Shank3-related ASD, yet the mechanisms underlying oligodendrocyte dysfunction and myelination deficits remain poorly characterized,” wrote Yuhua Ma, Helen Friedericke Bauer and their colleagues in their paper.

“We demonstrate that Shank3 deficiency disrupts oligodendrocyte development by promoting oligodendrocyte precursor cell (OPC) proliferation while impairing functional maturation and myelination.”

The link between Shank3, white matter and oligodendrocytes

As part of their colleagues, Ma, Bauer and their colleagues examined mice that were missing the Shank3 gene and served a model of Shank3-related ASD. They specifically looked at the growth and maturation of oligodendrocytes in the mice’s brains and spinal cord, as well as the so-called Erk signaling pathway.

This is a molecular pathway that is known to control the growth and maturation of cells. The researchers explored whether the lack of Shank3 in the mice affected the maturation of OPC. They also used drugs to block Erk signaling and investigated the effects of these drugs on the production of myelin.

“Mechanistically, Shank3 deficiency induced hyperactivation of the Erk signaling pathway, which compromised oligodendrocyte maturation and contributes to hypomyelination,” wrote the authors. “Pharmacological inhibition of the Erk pathway effectively restored oligodendrocyte maturation in vitro, rescued myelination deficits in vivo, and partially improved autism-related behaviors and motor function in Shank3-deficient mice.”

Overall, the team found that a loss of Shank3 adversely impacted the growth of OPCs, which in turn was linked to the production of too little myelin (i.e., hypomyelination). In addition, they showed that a molecule that triggers an overactivation of the Erk signaling pathway (i.e., Wnt5a) worsened disruptions in the production of myelin.

“Transcriptomic analyses further revealed dysregulation of Wnt signaling, particularly the upregulation of Wnt5a, a key ligand of the non-canonical Wnt pathway, in Shank3-deficient oligodendrocytes,” wrote Ma, Bauer and their colleagues. “Consistently, Wnt5a treatment was found to activate Erk signaling in primary oligodendrocytes and replicate the observed myelination deficits.”

A new promising therapeutic target

The results of this recent study highlight the key role of the Erk signaling pathway in the disrupted growth of OPCs and white matter abnormalities linked to some forms of ASD, specifically those marked by the absence or loss of the Shank3 gene. This pathway could thus be a promising therapeutic target, as drugs reducing its activation could help to restore myelination processes, potentially improving treatment outcomes for some individuals diagnosed with ASD.

“These findings uncover the Wnt5a-Erk axis as a critical regulator of oligodendrocyte dysfunction in Shank3-related ASD and highlight its therapeutic potential for addressing associated white matter deficits,” wrote the authors.

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