Redundancy and divergence in the amyloid precursor protein family

Abstract

a b s t r a c tGene duplication provides genetic material required for functional diversification. An interesting example is the amyloid precursor protein (APP) protein family. The APP gene family has experienced both expansion and contraction during evolution. The three mammalian members have been studied quite extensively in combined knock out models. The underlying assumption is that APP, amyloid precursor like protein 1 and 2 (APLP1, APLP2) are functionally redundant. This assumption is primarily supported by the similarities in biochemical processing of APP and APLPs and on the fact that the different APP genes appear to genetically interact at the level of the phenotype in combined knockout mice. However, unique features in each member of the APP family possibly contribute to specification of their function. In the current review, we discuss the evolution and the biology of the APP protein family with special attention to the distinct properties of each homologue. We propose that the functions of APP, APLP1 and APLP2 have diverged after duplication to contribute distinctly to different neuronal events. Our analysis reveals that APLP2 is significantly diverged from APP and APLP1.

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

“…Prokaryotes, plants, and yeasts do not appear to possess members of the APP family of proteins. The evolutionary appearance of the APP family of proteins therefore seems to coincide with the evolution of the earliest nervous systems with functioning synapses (Shariati and De Strooper, 2013) but also coincides with other events such as the appearance of lipoprotein receptors (Dieckmann et al, 2010). Based on direct sequence comparisons of the three human APP family members, APLP1 may be the closest human homolog of the invertebrate APP-like proteins (APL-1 and APPL) (Joshi et al, 2009); however, evolutionary relationships are difficult to interpret as the APP family of genes has undergone multiple duplication events and development of different splice variants.…”

“…This finding could indicate functional redundancy where APLP2 can take over for both APP and APLP1 functions, whereas APP or APLP1 alone cannot compensate for the loss of the other two family members. Although the functions of APP, APLP1, and APLP2 may substantially overlap, it remains formally possible that APP paralogues have unrelated nonredundant functions where the net effect of the loss of different pathways leads to lethality in double-knockout mice (Shariati and De Strooper, 2013). Relevant in this context is the observation that APLP1 and APLP2 levels are not upregulated in APP knockout mice (Zheng et al, 1995); APP, APLP1, and APLP2 have different tissue distributions, and proteins that interact within the ectodomains of APP, APLP1, and APLP2 overlap only modestly (Bai et al, 2008).…”

Amyloid Precursor Protein (APP)/APP-like Protein 2 (APLP2) Expression Is Required to Initiate Endosome-Nucleus-Autophagosome Trafficking of Glypican-1-derived Heparan Sulfate

“…Manipulations of A␤ production may thus have deleterious effects upon HS function in the nucleus. The present findings may also contribute to an understanding of the physiological function of APP, which is still incomplete (36).…”

The Impact of the Branched-Chain Ketoacid Dehydrogenase Complex on Amino Acid Homeostasis in Arabidopsis

“…Expression divergence is often observed among paralogous gene pairs that can be due to modification of regulatory elements during evolution (Shariati and De Strooper, 2013), and likely results in function diversification (Stern and Orgogozo, 2008). To evaluate the degree of expression divergence, we compared the expression profiles of the four paralogous pairs.…”