Mental disorders affect millions of people around the world and also account for an increasingly significant proportion of medical expenses. A research team led by Dr. Yijuang Chern, a Distinguished Research Fellow in the Institute of Biomedical Sciences at Academia Sinica, recently found a new mechanism underlying DNA repair in neurons. Their findings contribute to the current understanding of diseases with defects in DNA repair (such as mental diseases and neurodegenerative diseases). This study was published on January 3, 2018 in Molecular Psychiatry.

Generally speaking, the human body automatically metabolizes extraneous free radicals and repairs DNA sequences that are damaged by free radicals to ensure that cells function properly. Recent studies have discovered that neurons in patients suffering from mental illnesses show excessive presence of free radicals and the inability to fully repair damaged DNA.

When damaged DNA sequences cannot be properly repaired, these abnormal sequences will be replicated, resulting in abnormal neurotransmission, compromising neuronal survival, and aggravating the development of psychotic disorders. Therefore, how to restore and fix defective DNA repair mechanisms in neurons is a critical area of focus in research on mental disorders.

In their recent study, Dr. Chern and her team discovered a brand new complex that is related to the DNA repair mechanism in neurons—TDG complex. The TDG complex consists of TRAX (translin-associated protein X), DISC1 (disrupted-in-schizophrenia 1), and GSK3β (glycogen synthase kinase 3 beta). TRAX is an interacting protein of the C-terminus of A_2AR, which forms a complex with GSK3β and a risk gene for schizophrenia (DISC1).

Past research has found that TRAX and DISC1 are proteins associated with mental disorders and that GSK3β kinase is associated with the ability to regulate DNA repair mechanisms. Lithium, a drug commonly used to treat Alzheimer's disease, bipolar disorder, schizophrenia and other psychotic conditions, applies this finding by inhibiting GSK3β kinase in cells to slow down the progress of degenerative brain disorders and prevent deterioration in mental disorders.

Dr. Chern’s team has studied the A_2A adenosine receptor (A_2AR) located on the membrane of neurons over a long period of time. Her lab most recently discovered that the A_2AR receptor is key in the repair of neuron membranes. Activation of A_2AR leads to dissociation of the TRAX/DISC1/GSK3β complex (TDG complex).

This is of great interest because TRAX plays a critical role in detecting DNA damage by directly interacting with ATM to trigger the DNA repair machinery. Dissociation of the TDG complex facilitates the release of TRAX from the TDG complex and allows TRAX to enter the nucleus to facilitate DNA repair and subsequently enhance neuronal survival. Collectively, the TDG complex might serve as a potential therapeutic target for the development of novel treatments for diseases resulting from defects in DNA repair.

Although tremendous efforts have been devoted to the development of therapeutic treatments for mental disorders over the past decades, many important aspects regarding these disorders remained elusive. Findings regarding the TDG complex from this study offers new insight for illnesses resulting from deficiencies in DNA repair mechanisms and is expected to aid the development of new treatments for mental illnesses and neurodegenerative diseases in the future.

Dr. Chern and her team’s research article entitled “GSK3β negatively regulates TRAX, a scaffold protein implicated in mental disorders, for NHEJ-mediated DNA repair in neurons” is available at: https://www.nature.com/articles/s41380-017-0007-z?WT.feed_name=subjects_cell-biology