TY - JOUR
T1 - Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte–myelin dysfunction
AU - Vasistha, Navneet A.
AU - Johnstone, Mandy
AU - Barton, Samantha K.
AU - Mayerl, Steffen E.
AU - Thangaraj Selvaraj, Bhuvaneish
AU - Thomson, Pippa A.
AU - Dando, Owen
AU - Grünewald, Ellen
AU - Alloza, Clara
AU - Bastin, Mark E.
AU - Livesey, Matthew R.
AU - Economides, Kyriakos
AU - Magnani, Dario
AU - Makedonopolou, Paraskevi
AU - Burr, Karen
AU - Story, David J.
AU - Blackwood, Douglas H. R.
AU - Wyllie, David J. A.
AU - Mcintosh, Andrew M.
AU - Millar, J. Kirsty
AU - ffrench-constant, Charles
AU - Hardingham, Giles E.
AU - Lawrie, Stephen M.
AU - Chandran, Siddharthan
PY - 2019/11
Y1 - 2019/11
N2 - 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.
AB - 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.
U2 - 10.1038/s41380-019-0505-2
DO - 10.1038/s41380-019-0505-2
M3 - Article
SN - 1359-4184
VL - 24
SP - 1641
EP - 1654
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 11
ER -