1. Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction.
- Author
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Vasistha NA, Johnstone M, Barton SK, Mayerl SE, Thangaraj Selvaraj B, Thomson PA, Dando O, Grünewald E, Alloza C, Bastin ME, Livesey MR, Economides K, Magnani D, Makedonopolou P, Burr K, Story DJ, Blackwood DHR, Wyllie DJA, McIntosh AM, Millar JK, Ffrench-Constant C, Hardingham GE, Lawrie SM, and Chandran S
- 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
- 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.
- Published
- 2019
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