Structural and functional characterization of a novel FE65 protein product up-regulated in cognitively impaired FE65...

FE65 is a multi-modular adaptor protein that binds the cytoplasmic tail of the beta-amyloid precursor protein (APP). Genetic evidence suggests that APP is intimately involved in the pathogenesis of dementias of the Alzheimer type, neurodegenerative disorders that affect multiple cognitive domains, including learning and memory. Evidence from p97FE65-specific knockout mice (lacking the 97 kDa full-length FE65 protein, p97FE65) suggests an important role for FE65 in learning and memory. Interpretation of the learning and memory phenotype, however, is complicated by the up-regulation (compared with wild-type mice) of a novel 60 kDa FE65 isoform (p60FE65). Here, we report an evidence that p60FE65 is translated from an alternative methionine, M261, on the p97FE65 transcript. Thus, p60FE65 has a shortened N-terminus, lacking part of the WW domain that is considered important for nuclear translocation and transactivation of gene expression. Consistently, p60FE65 exhibits an attenuated ability for APP-Gal4-mediated transcription as compared with p97FE65. Similar to p97FE65, however, both transfected and endogenous p60FE65 are able to translocate to the nucleus in cultured cells and in neurons. These results are consistent with earlier evidence from our laboratory that reduced FE65 nuclear signaling may contribute, in part, to the phenotypes observed in p97FE65 knockout mice.