Mutations in the ALS2 gene cause juvenile onset amyotrophic lateral sclerosis, also known as motor neurone disease (MND) (1, 2). MND is a devastating neurodegenerative disorder causing a progressive paralysis. The ALS2 gene encodes the 180kD protein alsin, which has guanine nucleotide exchange (GEF) activity for Rab5 and Rac1 (3), thereby implicating a role in endosome fusion and intracellular trafficking. ALS2-deficient mice do not show an obvious MND-like phenotype, although they do show irregularities in endosome trafficking (4). We are investigating the role of the N-domain, which has sequence homology to RCC1 (regulator of chromatin condensation-1), a known beta-propeller structure. We have predicted the N-terminal domain of alsin using comparative modelling, and propose it is likely to form a seven-bladed beta propeller structure containing a disordered loop located within one of the blades. The propeller, like RCC1, is formed of anti-parallel beta-sheet blades radially arranged around a hydrophobic core. We aim to use circular dichroism to confirm the secondary structure, thereby providing practical evidence for the model. Beta-propeller structures are often sites of protein-protein interaction. We investigated whether the N-terminal of alsin contains protein interaction surfaces by using complementary and parallel techniques of co-immunoprecipitation, a yeast-2-hybrid screen and GST-pulldown. Preliminary findings have identified microtubule-associated proteins, neurofilaments, as well as proteins involved in endo- and exocytosis and associated with synaptic vesicles. These results are consistent with a role for alsin in endosome trafficking and axon maintenance, and strengthen well-established findings that neurofilament proteins are of high importance in MND pathology. We are now in the process of confirming these interactors, using human and mouse alsin constructs in parallel to investigate possible interspecies differences.