NDE1 in the DISC1 pathway: interactions of schizophrenia-related proteins
Date
2009Author
Bradshaw, Nicholas James
Metadata
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.