NDE1 in the DISC1 pathway: interactions of schizophrenia-related proteins

Abstract

The Disrupted-In-Schizophrenia 1 (DISC1) gene is one of the most established risk genes for psychiatric illness currently being studied, having originally been identified as being directly disrupted by a balanced chromosomal translocation that cosegregates with schizophrenia and other major mental illness a large Scottish family. The DISC1 protein is believed to act as a molecular scaffold within the cell, binding to a large number of other proteins. Three of these protein interactors, Phosphodiesterase 4B (PDE4B), Nuclear Distribution Factor E (Aspergillus nidulans)-homologue 1 (NDE1) and NDE-Like 1 (NDEL1) all have evidence implicating them as schizophrenia-related proteins in their own right. NDE1 and NDEL1 are highly similar proteins which are known to play cellular roles including microtubule function and mitosis. Their orthologues have also been shown to be important in neurodevelopment within the mouse brain. To date, most work in the literature has investigated NDEL1, with few focusing on NDE1. In the thesis, I first seek to establish a basic biology for NDE1 by the identification of splice variants expressed in the brain, establishing cellular localisation patterns within the cell and investigating NDE1 multimerisation. The relationship between NDE1 and NDEL1 is also investigated, with the two being found to form complexes together and to have partially over-lapping expression patterns within the cell. That NDE1 and DISC1 directly interact is confirmed. The relationship between NDE1 and PDE4B is then investigated, with the two proteins found to complex within the cell. Additionally, it is shown that NDE1 can be phosphorylated by protein kinase A (PKA). This kinase is cAMP dependant, and is thus indirectly regulated by the cAMP-degrading action of PDE4B protein. Attempts to map and analyse the effect of this phosphorylation on NDE1 are made.