DISC1–NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1

Abstract

Disrupted-In-Schizophrenia-1 (DISC1) is a unique susceptibility gene for major mental conditions, because of the segregation of its genetic variant with hereditary psychosis in a Scottish pedigree. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. The DISC1 protein is multifunctional, and a pool of DISC1 in the dynein motor complex is required for neurite outgrowth in PC12 cells as well as proper neuronal migration and dendritic arborization in the developing cerebral cortex in vivo. Here, we show that a specific interaction between DISC1 and nuclear distribution element-like (NDEL1/NUDEL) is required for neurite outgrowth in differentiating PC12 cells. Among several components of the dynein motor complex, DISC1 and NDEL1 are selectively upregulated during neurite outgrowth upon differentiation in PC12 cells. The NDEL1 binding site of DISC1 was narrowed down to a small portion of exon 13, corresponding to amino acids 802-835 of DISC1. We demonstrate that genetic variants of DISC1, proximal to the NDEL1 binding site, affect the interaction between DISC1 and NDEL1.

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

“…34,57 The experiments showed a significant decrease in the protein levels of LIS1, an interacting protein that forms a molecular complex with DISC1 and NUDEL and is involved in neuronal development. 24,26,28 The decrease in LIS1 expression in our mouse model is similar to a recent observation in our PC12 cell stable model of inducible expression, 57 indicating that the similar mechanisms of mutant hDISC1 action may occur in cell and mouse models. Another intriguing aspect of decreased levels of LIS1 in transgenic mice is its similarity to the reduced expression of LIS1 in the brain tissue from patients with schizophrenia.…”

“…26,27 DISC1-NUDEL-LIS1 interaction has been implicated in neurite outgrowth in PC12 cells and axon elongation in primary neurons. [28][29][30] In addition, alterations in the interaction of DISC1 with phosphodiesterase 4B have been suggested to contribute to the pathogenesis of major mental disorders. 31 Possible outcomes of the translocation in the DISC1 gene include haploinsufficiency or the production of a mutant-truncated DISC1 protein.…”

The DISC locus in psychiatric illness

“…56,[65][66][67]69,71,75,76,[84][85][86][87][88][89][90] Evidence from studies of endogenous DISC1 strongly supports a cytoplasmic localization and endogenous DISC1 immunoreactivity has been shown to overlap with that of F-actin, 76 a-tubulin, 84,85 MAP2 85 and gelsolin 65 supporting an interaction between DISC1 and the cytoskeleton. Endogenous DISC1 has also been colocalized with markers of the mitochondria 56,65,71,85 and centrosome.…”

“…Endogenous DISC1 has also been colocalized with markers of the mitochondria 56,65,71,85 and centrosome. 66,75 In primary and established neuronal cell types, DISC1 expression is localized to the cell body, nucleus and neurites 56,65,69,85,87,88 (Figure 1c).…”

“…As such, the regions of protein binding and association show considerable overlap such that genetic variation at the amino acid level may impact upon a multitude of DISC1 protein interactions. The only proteinbinding regions not contained within an overlapping haplotype is one of the reported NDEL1-binding regions, the LIS1-binding region and the GRB2 SH3-binding interaction motif; however, it has been reported that the Ser704Cys polymorphism affects DISC1 binding to NDEL1 75 and as it is in even closer proximity to the LIS1-and GRB2-binding regions, it is possible that it may also exert effects on binding of these proteins. References for the data in this figure are denoted by superscripted numbers with the exception of Murdoch et al, 68 which is indicated with an arrow.…”