Physical and genetic interaction of filamin with presenilin in Drosophila.

Presenilins were first identified as causative factors in early onset, familial Alzheimer's Disease (FAD). They are predicted to encode a highly conserved novel family of eight transmembrane domain proteins with a large hydrophilic loop between TM6 and TM7 that is the site of numerous FAD mutations. Here, we show that the loop region of Drosophila and human presenilins interacts with the C-terminal domain of Drosophila filamin. Furthermore, we show that Drosophila has at least two major filamin forms generated by alternative splicing from a gene that maps to position 89E10-89F4 on chromosome 3. The longest form is enriched in the central nervous system and ovaries, shares 41.7% overall amino acid identity with human filamin (ABP-280) and contains an N-terminal actin-binding domain. The shorter form is broadly expressed and encodes an alternatively spliced form of the protein lacking the actin-binding domain. Finally, we show that presenilin and filamin are expressed in overlapping patterns in Drosophila and that dominant adult phenotypes produced by overexpression of presenilin can be suppressed by overexpression of filamin in the same tissue. Taken together, these results suggest that presenilin and filamin functionally interact during development.