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@ARTICLE{Ma:285735,
author = {Ma, Yuhua and Bauer, Helen Friedericke and Bockmann,
Juergen and Schön, Michael and Boeckers, Tobias M and Lutz,
Anne-Kathrin},
title = {{S}hank3 related oligodendrocyte alterations in autism are
restored by {E}rk pathway inhibition.},
journal = {Molecular psychiatry},
volume = {31},
number = {4},
issn = {1359-4184},
address = {[London]},
publisher = {Springer Nature},
reportid = {DZNE-2026-00292},
pages = {1880 - 1897},
year = {2026},
abstract = {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.},
keywords = {Animals / Male / Mice / Autistic Disorder: genetics /
Autistic Disorder: metabolism / Autistic Disorder:
physiopathology / Corpus Callosum: metabolism / Corpus
Callosum: physiopathology / MAP Kinase Signaling System /
Mice, Knockout / Molecular Targeted Therapy / Myelin Sheath:
genetics / Myelin Sheath: metabolism / Oligodendroglia:
physiology / Primary Cell Culture / White Matter: metabolism
/ White Matter: physiopathology / Microfilament Proteins:
deficiency / Microfilament Proteins: genetics / Nerve Tissue
Proteins: deficiency / Nerve Tissue Proteins: genetics /
Shank3 protein, mouse (NLM Chemicals) / Microfilament
Proteins (NLM Chemicals) / Nerve Tissue Proteins (NLM
Chemicals)},
cin = {AG Böckers},
ddc = {610},
cid = {I:(DE-2719)1910002},
pnm = {352 - Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41203933},
pmc = {pmc:PMC12999492},
doi = {10.1038/s41380-025-03333-1},
url = {https://pub.dzne.de/record/285735},
}