TY  - JOUR
AU  - Ma, Yuhua
AU  - Bauer, Helen Friedericke
AU  - Bockmann, Juergen
AU  - Schön, Michael
AU  - Boeckers, Tobias M
AU  - Lutz, Anne-Kathrin
TI  - Shank3 related oligodendrocyte alterations in autism are restored by Erk pathway inhibition.
JO  - Molecular psychiatry
VL  - 31
IS  - 4
SN  - 1359-4184
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2026-00292
SP  - 1880 - 1897
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Male
KW  - Mice
KW  - Autistic Disorder: genetics
KW  - Autistic Disorder: metabolism
KW  - Autistic Disorder: physiopathology
KW  - Corpus Callosum: metabolism
KW  - Corpus Callosum: physiopathology
KW  - MAP Kinase Signaling System
KW  - Mice, Knockout
KW  - Molecular Targeted Therapy
KW  - Myelin Sheath: genetics
KW  - Myelin Sheath: metabolism
KW  - Oligodendroglia: physiology
KW  - Primary Cell Culture
KW  - White Matter: metabolism
KW  - White Matter: physiopathology
KW  - Microfilament Proteins: deficiency
KW  - Microfilament Proteins: genetics
KW  - Nerve Tissue Proteins: deficiency
KW  - Nerve Tissue Proteins: genetics
KW  - Shank3 protein, mouse (NLM Chemicals)
KW  - Microfilament Proteins (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41203933
C2  - pmc:PMC12999492
DO  - DOI:10.1038/s41380-025-03333-1
UR  - https://pub.dzne.de/record/285735
ER  -