This is an important paper, which reports relevant information to understand the functional role of the Fe65 proteins. The results clearly demonstrate that the knockout of two members of the Fe65 protein family results in a phenotype similar to that observed in the APP/APLP1/APLP2 triple knockout, thus indicating that the APP-Fe65 complex plays a crucial role during development, as previously suggested by knockout experiments in the worm (Zambrano et al., 2002).

Although the molecular mechanism of the APP-Fe65 machinery is still unclear, two conclusions can be drawn:

1. The observed phenotype does not depend on misexpression or mislocalization or altered processing of APP induced by the absence of two Fe65s (the marginal decrease of Aβ42 seems to appear only in male mice and no difference between males and females in the brain phenotype is reported).

2. While the APP knockout phenotype was observed only in the triple knockout (Herms et al., 2004), Fe65L2 alone is unable to compensate for the absence of the other two members of the family (but the presence of Fe65L2...  Read more

This is an important paper, which reports relevant information to understand the functional role of the Fe65 proteins. The results clearly demonstrate that the knockout of two members of the Fe65 protein family results in a phenotype similar to that observed in the APP/APLP1/APLP2 triple knockout, thus indicating that the APP-Fe65 complex plays a crucial role during development, as previously suggested by knockout experiments in the worm (Zambrano et al., 2002).

Although the molecular mechanism of the APP-Fe65 machinery is still unclear, two conclusions can be drawn:

1. The observed phenotype does not depend on misexpression or mislocalization or altered processing of APP induced by the absence of two Fe65s (the marginal decrease of Aβ42 seems to appear only in male mice and no difference between males and females in the brain phenotype is reported).

2. While the APP knockout phenotype was observed only in the triple knockout (Herms et al., 2004), Fe65L2 alone is unable to compensate for the absence of the other two members of the family (but the presence of Fe65L2 could prevent identification of other functions of the Fe65 protein family).

References:
Zambrano N, Bimonte M, Arbucci S, Gianni D, Russo T, Bazzicalupo P. feh-1 and apl-1, the Caenorhabditis elegans orthologues of mammalian Fe65 and beta-amyloid precursor protein genes, are involved in the same pathway that controls nematode pharyngeal pumping. J Cell Sci. 2002 Apr 1;115(Pt 7):1411-22. Abstract

Herms J, Anliker B, Heber S, Ring S, Fuhrmann M, Kretzschmar H, Sisodia S, Muller U. Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J. 2004 Oct 13;23(20):4106-15. Epub 2004 Sep 23. Abstract

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