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Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction.
- Source :
-
Molecular psychiatry [Mol Psychiatry] 2019 Nov; Vol. 24 (11), pp. 1641-1654. Date of Electronic Publication: 2019 Sep 03. - Publication Year :
- 2019
-
Abstract
- Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption of  white matter integrity compared with familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) derived case oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced when  compared with controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.
- Subjects :
- Adult
Animals
Chromosomes, Human, Pair 1 genetics
Chromosomes, Human, Pair 11 genetics
Diffusion Tensor Imaging methods
Female
Humans
Induced Pluripotent Stem Cells metabolism
Male
Mental Disorders genetics
Mice
Middle Aged
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
White Matter metabolism
White Matter physiology
Myelin Sheath metabolism
Oligodendroglia metabolism
Translocation, Genetic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5578
- Volume :
- 24
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 31481758
- Full Text :
- https://doi.org/10.1038/s41380-019-0505-2