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

Navneet A. Vasistha, 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 MillarCharles ffrench-Constant, Giles E. Hardingham, Stephen M. Lawrie, Siddharthan Chandran

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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.

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

Cite this