PhD Project Proposal for Hilda Tsang
Project Supervisors: Dr Evan Reid, Department of Medical Genetics and Cambridge Institute for Medical Research, University of Cambridge, UK Professor J. Paul Luzio, Department of Clinical Biochemistry and Cambridge Institute for Medical Research, University of Cambridge, UK

This project is aimed at investigating in mammalian cells the function of NIPA1, an integral membrane protein which is mutated in some cases of autosomal dominant pure HSP. It will build on what we have already learned from Drosophila melanogaster models lacking or over-expressing the drosophila NIPA1 homologue spichthyin (Spic), generated as a result of a collaboration between our group and Dr Cahir O’Kane (Department of Genetics, University of Cambridge). Data from these models has given several important insights into the function of NIPA1 in Drosophila. They indicate the subcellular localisation of the Drosophila homologue of NIPA1, and that loss of the protein in neurons leads to abnormalities of the Drosophila neuromuscular junction, which are a consequence of abnormalities of a defined signalling pathway. Drosophila NIPA1 appears to be a novel inhibitor of this signalling pathway. The project will aim to test whether mammalian NIPA1 behaves in the same way as Drosophila NIPA1. We will examine the subcellular location of mammalian NIPA1, and examine the effects of cellular depletion of mammalian NIPA1 by small interfering RNA (siRNA) knockdown, in neuronal and non-neuronal cell lines. We will also examine the effects of over-expression of wild-type NIPA1, or expression of mutant forms of NIPA1