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

Vasistha, N. A.; Johnstone, M.; Barton, S.; Mayerl, S.; Thangaraj, B.; Dando, O.; Grunewald, E.; Alloza, C.; Bastin, M.; Livesey, M.; Economides, K.; Magnani, D.; Makedonopolou, P.; Burr, K.; Story, D.; Blackwood, D.; Wyllie, D.; McIntosh, A. M.; Millar, K. M.; ffrench-Constant, C.; Hardingham, G.; Lawrie, S.; Chandran, S.

doi:10.1101/657163

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bioRxiv · 10.1101/657163

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

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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 (DTI) 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 in white matter integrity compared to familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) case derived 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 compared to 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.

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Vasistha, N. A., Johnstone, M., Barton, S., Mayerl, S., Thangaraj, B., Dando, O., Grunewald, E., Alloza, C., Bastin, M., Livesey, M., Economides, K., Magnani, D., Makedonopolou, P., Burr, K., Story, D., Blackwood, D., Wyllie, D., McIntosh, A. M., Millar, K. M., ffrench-Constant, C., Hardingham, G., Lawrie, S., Chandran, S.. 2019-06-03. Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction. https://doi.org/10.1101/657163

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