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Mol Psychiatry ; 24(11): 1641-1654, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31481758

RESUMO

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.


Assuntos
Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Translocação Genética/genética , Adulto , Animais , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Transtornos Mentais/genética , Camundongos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Substância Branca/metabolismo , Substância Branca/fisiologia
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