Huntingtin, α-synuclein and the amyloid precursor protein (APP) are molecules familiar to most neuroscientists because of their involvement in several neurodegenerative disorders. But, as it turns out, we know little about their roles in healthy neurons. Two recent papers provide some clues as to the function of APP by showing that it might participate in the control of cell motility and gene expression.

Both studies initially focused on the well-characterized interaction between APP and another protein of unknown function — FE65. In addition to its interaction with APP, FE65 binds to Mena, a protein that is thought to participate in the regulation of actin dynamics. Sabo et al. co-expressed APP and FE65, and found that both proteins colocalized with Mena and integrins at cell-adhesion sites known as 'focal complexes' — dynamic membrane sites commonly located at the leading edge of migrating cells. Furthermore, by using a motility assay in which a scratch is made to a confluent cell layer, they found that cells expressing APP and FE65 migrated faster to 'heal the wound' compared with cells that only expressed APP.

But not all the action is at the membrane; the interaction between the cytoplasmic tail of APP and FE65 might also regulate nuclear gene expression. When the presenilins cleave APP, they produce β-amyloid and an intracellular segment. As the intracellular segment of other presenilin substrates can regulate transcription, Cao and Südhof explored whether the cytoplasmic tail of APP had a similar role. They found that a fusion protein between APP and the nuclear binding domain of Gal4 could activate gene expression only if FE65 was also present. Moreover, they discovered that the two proteins formed a complex with Tip60, a histone acetyltransferase that participates in DNA repair and transcription.

Although it remains to be seen whether native APP has similar functions in neurons, the results from both studies provide an intriguing insight into this enigmatic protein.