Home > In process > Shank3 related oligodendrocyte alterations in autism are restored by Erk pathway inhibition. > print

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024 7 _ |a 10.1038/s41380-025-03333-1
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024 7 _ |a 1359-4184
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024 7 _ |a 1476-5578
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037 _ _ |a DZNE-2026-00292
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Ma, Yuhua
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245 _ _ |a Shank3 related oligodendrocyte alterations in autism are restored by Erk pathway inhibition.
260 _ _ |a [London]
|c 2026
|b Springer Nature
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520 _ _ |a White matter abnormalities are consistently observed in Shank3-related autism spectrum disorders (ASD), yet the mechanisms underlying oligodendrocyte dysfunction and myelination deficits remain poorly characterized. Here, we demonstrate that Shank3 deficiency disrupts oligodendrocyte development by promoting oligodendrocyte precursor cell (OPC) proliferation while impairing functional maturation and myelination. Mechanistically, Shank3 deficiency induced hyperactivation of the Erk signalling pathway, which compromised oligodendrocyte maturation and contributes to hypomyelination. 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. Transcriptomic analyses furtherly revealed dysregulation of Wnt signalling, particularly the upregulation of Wnt5a, a key ligand of the non-canonical Wnt pathway, in Shank3-deficient oligodendrocytes. Consistently, Wnt5a treatment was found to activate Erk signalling in primary oligodendrocytes and replicate the observed myelination deficits. 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.
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650 _ 7 |a Shank3 protein, mouse
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650 _ 7 |a Microfilament Proteins
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650 _ 7 |a Nerve Tissue Proteins
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650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Autistic Disorder: genetics
|2 MeSH
650 _ 2 |a Autistic Disorder: metabolism
|2 MeSH
650 _ 2 |a Autistic Disorder: physiopathology
|2 MeSH
650 _ 2 |a Corpus Callosum: metabolism
|2 MeSH
650 _ 2 |a Corpus Callosum: physiopathology
|2 MeSH
650 _ 2 |a MAP Kinase Signaling System
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Molecular Targeted Therapy
|2 MeSH
650 _ 2 |a Myelin Sheath: genetics
|2 MeSH
650 _ 2 |a Myelin Sheath: metabolism
|2 MeSH
650 _ 2 |a Oligodendroglia: physiology
|2 MeSH
650 _ 2 |a Primary Cell Culture
|2 MeSH
650 _ 2 |a White Matter: metabolism
|2 MeSH
650 _ 2 |a White Matter: physiopathology
|2 MeSH
650 _ 2 |a Microfilament Proteins: deficiency
|2 MeSH
650 _ 2 |a Microfilament Proteins: genetics
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: deficiency
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: genetics
|2 MeSH
700 1 _ |a Bauer, Helen Friedericke
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700 1 _ |a Bockmann, Juergen
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700 1 _ |a Schön, Michael
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700 1 _ |a Boeckers, Tobias M
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700 1 _ |a Lutz, Anne-Kathrin
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773 _ _ |a 10.1038/s41380-025-03333-1
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