Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte–myelin dysfunction

Research output: Contribution to journal › Journal article › Research › peer-review

  • Mandy Johnstone
  • Samantha K. Barton
  • Steffen E. Mayerl
  • Bhuvaneish Thangaraj Selvaraj
  • Pippa A. Thomson
  • Owen Dando
  • Ellen Grünewald
  • Clara Alloza
  • Mark E. Bastin
  • Matthew R. Livesey
  • Kyriakos Economides
  • Dario Magnani
  • Paraskevi Makedonopolou
  • Karen Burr
  • David J. Story
  • Douglas H.R. Blackwood
  • David J.A. Wyllie
  • Andrew M. McIntosh
  • J. Kirsty Millar
  • Charles ffrench-Constant
  • Giles E. Hardingham
  • Stephen M. Lawrie
  • Siddharthan Chandran

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.

Original languageEnglish
JournalMolecular Psychiatry
Volume24
Issue number11
Pages (from-to)1641-1654
Number of pages14
ISSN1359-4184
DOIs
Publication statusPublished - 1 Nov 2019
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements We thank the individuals and their families who agreed to participate in this study. We are grateful to Dr Amanda Boyd, Mrs Carolyn Manson, and Mr John Agnew for help with animal care and to Mrs Nicola Clements, Mrs Karen Gladstone, and Mrs Rinku Rajan for generous help with tissue culture and Ms Sophie Glen for help with preparing RNA. We thank Dr Greg Polites and Dr Michel Didier for providing access to the Der1 mice. We are also grateful to Roslin Cells (UK) for excellent support with reprogramming of fibroblasts. This work was supported by a Medical Research Council grant to SC, JKM, and AMM, an EU 7th Framework Programme Grant (607616FP7) to JKM and generous funding from the MS Society to SC. NAV was supported by a Department of Biotechnology, Government of India fellowship. MJ is supported by a Wellcome Trust Clinical Career Development Fellowship and The Sackler Foundation. MRL is supported by Royal Society of Edinburgh/Caledonian Research Fund Personal Research Fellowship. The imaging work was originally supported by an award from the Translational Medicine Research Collaboration—a consortium made up of the Universities of Aberdeen, Dundee, Edinburgh, and Glasgow, the four associated NHS Health Boards (Grampian, Tayside, Lothian, and Greater Glasgow and Clyde), Scottish Enterprise, and Pfizer.

Publisher Copyright:
© 2019, The Author(s).

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