Mutations of DISC1 encoding gene – a human gene that regulates various cellular activities including neurogenesis, or the birth of neurons – are known to be associated with major psychiatric disorders for over a decade. However, how the DISC1 protein interacts with many other proteins to impact human brain development has remained unknown until recently.
A research team uncovered the never before known high-resolution structure of DISC1 protein in complex with Ndel1 – a vital protein for neurogenesis and many other aspects of brain functions. The team found that if the formation of DISC1/Ndel1 complex was disrupted by mutations of DISC1 gene, neurogenesis will be delayed and thus may cause mental disorders. Their findings were published in a leading neuroscience journal Neuron.
Authors show that DISC1 regulates Ndel1’s kinetochore attachment, but not its centrosome localization, during mitosis. Functionally, disrupting DISC1/Ndel1 complex formation prolongs mitotic length and interferes with cell-cycle progression in human cells, and it causes cell-cycle deficits of radial glial cells in the embryonic mouse cortex and human forebrain organoids.
They also observed similar deficits in organoids derived from schizophrenia patient induced pluripotent stem cells (iPSCs) with a DISC1 mutation that disrupts its interaction with Ndel1.
“We uncovered a new mechanism of action for DISC1 gene based on its structure, and offered implications of how genetic insults may contribute to schizophrenia and other serious psychiatric disorders,” said the senior author.
“The DISC1/Ndel1 structure and their interaction during neurogenesis in animal models and schizophrenia patient-derived human forebrain organoids provide a potential pathological understanding of complex psychiatric disorders that may help the development of new treatments and drugs,” said lead author of the paper.
Mechanism of Schizophrenia
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