New mechanism of action for DISC1, psychiatric disorder agent, revealed by scientists

December 13, 2017

DISC1 (disrupted-in-schizophrenia 1), originally identified in a large Scottish family suffering from multiple psychiatric disorders due to a chromosomal translocation-induced disruption, has been established as a genetic risk factor for a wide array of psychiatric disorders, including schizophrenia, bipolar disorder, major depression, and autism spectrum disorders. Unmatched to the wealth of functional and pathological data on DISC1, biochemical and structural characterizations of DISC1 and its interactions with target proteins are very scarce.

In a recent study, scientists from the Hong Kong University of Science and Technology in a close collaboration with a team from the Perelman School for Medicine, University of Pennsylvania solved the high-resolution structure of DISC1 in complex with Ndel1, uncovering a new mechanism of action for DISC1 based on its structure, which can lead to implications for how genetic insults may contribute to psychiatric disorders.

Their findings were published in Neuron on November 1, 2017 (DOI: 10.1016/j.neuron.2017.10.010).

"Our study revealed that mechanistically, DISC1 regulates Ndel1's kinetochore attachment, but not its centrosome localization, during mitosis," said Professor Zhang Mingjie, Kerry Holdings Professor of Science and leader of the research group. "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 neuronal stem cells in the embryonic mouse cortex and human forebrain organoids. We 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." Professor Zhang further added: "This is a multifaceted research efforts spanning very broad research areas and taking about 8 years to complete. We are especially thankful to our collaborators from the University of Pennsylvania, who have contributed much to the functional aspects of the paper using human brain organoids as the model system."

"The findings uncovered a new mechanism of action for DISC1 based on its structure and has implications for how genetic insults may contribute to psychiatric disorders," said Ye Fei, a leading author of the paper. "We characterized the binding properties between DISC1 and Ndel1. This structural insight into the DISC1/Ndel1 complex allowed us to develop a highly specific approach to study the function of their interaction by designing a highly specific peptide, which only inhibits the formation of the DISC1/Ndel1 complex but does not interfere with the bindings of these two proteins to many other target proteins."

"Based on structural insights, we identified a function of DISC1/Ndel1 interaction in regulating cell-cycle progression of neuronal stem cells in an animal model and in human forebrain organoids," said professor Zhang. "Our study from patient-derived forebrain organoids provides a potential mechanistic understanding of how DISC1 mutation with its C-terminal deletion can affect neural developmental processes, and insight into mechanisms of pathogenesis of complex psychiatric disorders."
-end-


Hong Kong University of Science and Technology

Related Psychiatric Disorders Articles from Brightsurf:

Sexual minorities, especially women, who misuse substances more likely to have psychiatric disorders
More than half of lesbian, gay and bisexual individuals who misuse alcohol or tobacco also have a co-occurring psychiatric disorder, compared to one-third of heterosexuals, a new University of Michigan study finds.

Internet gaming youth not more prone to psychiatric disorders
Children who show addiction-like gaming signs are not any more susceptible to mental health problems than their non-gaming peers.

People with coronavirus symptoms more likely to have psychiatric disorders and loneliness
People who have or had COVID-19 symptoms are more likely to develop general psychiatric disorders and are lonelier, with women and young people more at risk, says a just-published study co-authored at Cambridge Judge Business School.

Brain structural elements in psychiatric disorders
While researchers have previously identified brain structural signatures associated with individual neurological diseases using techniques such as magnetic resonance imaging (MRI), a team of scientists based in Germany, in a new study, has compared data from multiple studies to find brain structural abnormalities shared between four different neuropsychiatric conditions.

Psychiatric disorders after first birth reduce likelihood of subsequent children
Women who suffer from psychiatric disorders such as depression, anxiety, mania and schizophrenia following the live birth of their first child are less likely to go on to have more children, according to the first study to investigate this in a large nationwide population.

International study completes the largest genetic map of psychiatric disorders so far
An international study published in the journal Cell, has described 109 genetic variants associated with eight psychiatric disorders: autism, ADHD, schizophrenia, bipolar disorder, depression, obsessive-compulsive disorder and Tourette Syndrome, in a total of about 230,000 patients worldwide.

Are there shared genetic factors between weight and major psychiatric disorders?
Data from 1.3 million people were used to investigate genetic overlap between body mass index and major psychiatric disorders such as schizophrenia, bipolar disorder and major depression.

How are psychiatric disorders linked to infections during pregnancy?
Severe infections during pregnancy have been connected to a range of psychiatric disorders by different studies in humans and animals.

Repeated febrile convulsions linked to epilepsy and psychiatric disorders
The risk of febrile convulsions increases with the child's fever, and children who suffer from repeated febrile convulsions during their first year of life have an increased risk of developing epilepsy and psychiatric disorders later in life.

Serum neurofilament is a discriminative biomarker between frontotemporal dementia and psychiatric disorders
Early symptoms of frontotemporal dementia are often confused with symptoms occurring in psychiatric disorders.

Read More: Psychiatric Disorders News and Psychiatric Disorders Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.