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Review
. 2017 Mar 30:10:87.
doi: 10.3389/fnmol.2017.00087. eCollection 2017.

APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins

Suzanne Guénette  1 , Paul Strecker  2 , Stefan Kins  2
Affiliations
Review

APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins

Suzanne Guénette et al. Front Mol Neurosci. .

Abstract

Understanding the molecular mechanisms underlying amyloid precursor protein family (APP/APP-like proteins, APLP) function in the nervous system can be achieved by studying the APP/APLP interactome. In this review article, we focused on intracellular APP interacting proteins that bind the YENPTY internalization motif located in the last 15 amino acids of the C-terminal region. These proteins, which include X11/Munc-18-interacting proteins (Mints) and FE65/FE65Ls, represent APP cytosolic binding partners exhibiting different neuronal functions. A comparison of FE65 and APP family member mutant mice revealed a shared function for APP/FE65 protein family members in neurogenesis and neuronal positioning. Accumulating evidence also supports a role for membrane-associated APP/APLP proteins in synapse formation and function. Therefore, it is tempting to speculate that APP/APLP C-terminal interacting proteins transmit APP/APLP-dependent signals at the synapse. Herein, we compare our current knowledge of the synaptic phenotypes of APP/APLP mutant mice with those of mice lacking different APP/APLP interaction partners and discuss the possible downstream effects of APP-dependent FE65/FE65L or X11/Mint signaling on synaptic vesicle release, synaptic morphology and function. Given that the role of X11/Mint proteins at the synapse is well-established, we propose a model highlighting the role of FE65 protein family members for transduction of APP/APLP physiological function at the synapse.

Keywords: FE65; FE65L1; X11/Mint proteins; amyloid precursor protein (APP); synaptic signaling.

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Figures

Figure 1
Figure 1
Schematic overview of postulated FE65 protein family function at the synapse. Reported interaction partners for the FE65 protein family are displayed at different synaptic sites, such as the active zone and the PSD. However, these interactions may also take place in other subsynaptic compartments. The individual FE65-interacting proteins were sorted into different functional units: regulation of Ca2+-homeostasis (gray), actin remodeling (yellow), vesicle-associated proteins involved in neurotransmitter release (green), cell adhesion (dark blue) and other surface receptor proteins (light blue). The FE65 binding receptors in bold are those implicated in signal transduction pathways known to alter synaptic function. The PSD, active zone, actin cytoskeleton and neurotransmitter receptors are highlighted in different colors. RYR, Ryanodine receptor; SERCA 2, sarcoplasmatic/endoplasmatic reticulum calcium ATPase 2; Arf6, ADP-ribosylation factor 6; Rac1, Ras-related C3 botulinum toxin substrate 1; VGLUT1, vesicular glutamate transporter 1; SV2A, synaptic vesicle glycoprotein 2A; LRP1, low-density lipoprotein receptor-related protein; ApoER2, apolipoprotein E receptor 2; VLDLR, very low-density lipoprotein receptor; APP, amyloid precursor protein; APLPs, APP-like proteins (1 and 2); P2X2, P2X purinergic receptor 2; NCAM2, neural cell adhesion molecule 2; L1CAM, neural cell adhesion molecule L1; PSD, post-synaptic density; PTB1 and PTB2, phosphotyrosine-binding domain 1 and 2; WW, protein domain containing two tryptophans.
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