Naslov
NDE1 interacts with DISC1: A link between schizophrenia-related genes

Autori
Bradshaw, N. J. ; Christe, S. ; Mackie, S. ; Soares, D. C. ; Porteous D. J. ; Millar, J. K.

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Skup
15th International Student Congress of Medical Sciences

Mjesto i datum
Groningen, Nizozemska, 03.06.2008. - 06.06.2008

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Schizophrenia ; DISC1 ; NDE1

Sažetak
Introduction Disrupted-In-Schizophrenia 1 (DISC1) is among the most promising schizophrenia candidate genes currently being studied. Information on its biological function is, however, still limited. DISC1 is known to bind to NDEL1, a protein which has a role in neuronal migration, providing a potential model for schizophrenia pathology. NDEL1 has a close homolog, NDE1, which has recently been independently associated with schizophrenia in the Finnish population. It would therefore be interesting to know if NDE1 also plays a role in the DISC1 pathway. Materials & Methods Various molecular biology techniques were used to investigate the interaction of NDE1 with DISC1 and other proteins, including co-immunoprecipitation and immunocytochemistry. These were done primarily in human and mammalian cultured cell lines. PCR on commercially available cDNA from human brain was used to investigate the existence of different theoretical NDE1 isoforms. Finally several biochemical techniques were used to evaluate the phosphorylation status of NDE1 in cells and in vitro. Results We demonstrate the existence of several different splice variants of NDE1, all of which are present in the human brain, sometimes in differing expression patterns. Using multiple antibodies, NDE1 can be seen to localise at the nucleus and centrosome, differing from the known expression patterns of NDEL1. The exact staining pattern within the nucleus appears to be isoform dependant. Like NDEL1, we found NDE1 forms a homodimer, but we also have evidence for an interaction between NDE1 and NDEL1. Crucially, NDE1 and DISC1 interact with each other in cell lines, confirming previous yeast-2-hybrid studies. Finally, we show evidence that NDE1 can be phosphorylated by PKA. This kinase is regulated by PDE4B, another DISC1 interactor and independent schizophrenia candidate gene. Conclusion We have shown NDE1 to have a complex splicing and expression pattern within the human brain. It appears to play differing cellular roles to its close homolog NDEL1, although the two are capable of forming a complex with each other. In addition to being a schizophrenia candidate gene in its own right, NDE1 interacts with DISC1 and is potentially linked to a third schizophrenia candidate gene, PDE4B, through DISC1 interaction and PKA phosphorylation. This pathway would therefore appear to be a good starting point from which to build up a wider picture of the cellular pathology of schizophrenia.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti, Biotehnologija

POVEZANOST RADA