The psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function

Abstract

Disrupted in schizophrenia 1 (DISC1), a genetic risk factor for multiple serious psychiatric diseases including schizophrenia, bipolar disorder and autism, is a key regulator of multiple neuronal functions linked to both normal development and disease processes. As these diseases are thought to share a common deficit in synaptic function and architecture, we have analyzed the role of DISC1 using an approach that focuses on understanding the protein– protein interactions of DISC1 specifically at synapses. We identify the Traf2 and Nck-interacting kinase (TNIK), an emerging risk factor itself for disease, as a key synaptic partner for DISC1, and provide evidence that the DISC1–TNIK interaction regulates synaptic composition and activity by stabilizing the levels of key postsynaptic density proteins. Understanding the novel DISC1–TNIK interaction is likely to provide insights into the etiology and underlying synaptic deficits found in major psychiatric diseases.

PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence

“…In contrast, biological studies of DISC1 have been rigorously taken place based on solid discovery of the DISC1 gene in the original Scottish pedigree, indicating that the DISC1 pathway can underlie the endophenotypes relevant to a wide range of psychiatric disorders, in particular, schizophrenia and depression (2). DISC1 interacts with many proteins, and its regulatory roles in synaptic plasticity may be multiple (10,12,19,20). It remains elusive how these multiple mechanisms interact with each other for the overall synaptic phenotypes.…”

“…Thus far, more than one mechanism has been proposed in regard to the regulation of synaptic plasticity and maintenance by DISC1 (10,19,20). For example, DISC1 negatively regulates access of Kalirin-7 (Kal-7) to a small GTPase protein Rac1 and contributes to proper control of Rac1 activation and synaptic maintenance: this mechanism participates in the spine change triggered by NMDA-R activation (10).…”

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner

“…DISC1 is a scaffolding protein that is thought to coordinate other synaptic proteins (30)(31)(32), and indeed plays a key role in synaptic spine maintenance in association with the activation of NMDA receptors (33). Thus, we hypothesized that the results from the unbiased approach might reflect a possible defect of a molecular pathway involving DISC1 in the synapse.…”

DISC1 Protein Regulates γ-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons

“…It has been found that DISC1 interacts with multiple proteins, such as the second messenger PDE4B, which hydrolyzes cAMP and regulates the PKA signaling pathway (4), the transcription factor ATF4/CREB2, which controls gene expression (38), and the motor protein kinesin 1, which mediates the microtubule-based transport of neuronal cargos (32). The role of DISC1 in regulating glutamate receptors and spine synapses has been documented (17)(18)(19). In this study, we revealed the role of DISC1 in regulating GABA A receptors and synaptic inhibition.…”

“…DISC1 is enriched in the postsynaptic density of excitatory synapses (16), where it regulates spine size, spine number, and AMPA receptor synaptic trafficking via a kalirin 7-Rac1-PAK pathway (17). DISC1 also regulates synapse maintenance through interacting with TRAF2 and NCK-interacting protein kinase (TNIK) (18) and exerts an important effect on NMDA receptor expression and function through a mechanism depending on the transcription factor cAMP response elementbinding protein (19). DISC1 has also been found at inhibitory synapses (16).…”