Neddylation dysfunction in Alzheimer's disease

Abstract

Ubiquitin-dependent proteolysis is a major mechanism that downregulates misfolded proteins or those that have finished a programmed task. In the last two decades, neddylation has emerged as a major regulatory pathway for ubiquitination. Central to the neddylation pathway is the amyloid precursor protein (APP)-binding protein APP-BP1, which together with Uba3, plays an analogous role to the ubiquitin-activating enzyme E1 in nedd8 activation. Activated nedd8 covalently modifies and activates a major class of ubiquitin ligases called Cullin-RING ligases (CRLs). New evidence suggests that neddylation also modifies Type-1 transmembrane receptors such as APP. Here we review the functions of neddylation and summarize evidence suggesting that dysfunction of neddylation is involved in Alzheimer's disease.

Fig. 1

Neddylation activates ubiquitination of E3 ligase CRLs. A typical SCF complex (purple) is used as an example of a CRL. The activity of CRL is controlled by two major pathways: 1) ubiquitin (Ub) is activated by E1 and transferred to Cul1 by E2, and 2) Cul1 is covalently modified by Nedd8 (N8) via the BP1-activated neddylation pathway. Neddylation changes Cul1 into its active conformation for ubiquitination of the target protein β-catenin, which binds to the substrate receptor βTrCP1. Skp1 is the adaptor that bridges Cul1 and βTrCP1. The neddylation pathway is also regulated by COP9, CAND1, and ASPP2. Green arrows indicate recycling of the components.

Fig. 2

APP Processing and signaling is regulated by neddylation. A. The C-terminal sequence of APP₆₉₅ showing the lysine residues and the γ-secretase cleavage sites. B. The conservation of APP, APLP1, and APLP2. The human sequences were aligned and analyzed by Praline. *, the positions of the APP lysine residues.

Fig. 3

BP1 and nedd8 protein expression in mouse and human brains. A. BP1 was expressed in normal mouse brain hippocampus. Paraffin-embedded, adult C57BL/6 mouse brain sections were immunostained with rabbit anti-BP1 (BP339) [19] coupled with Alexa fluor 564 goat anti-rabbit (Invitrogen). The nucleus was stained with DAPI. Some pyramidal cells were positive for BP1. Cells in the dentate granule cell layer, especially those near the subgranular zone, were positive for BP1. B. Nedd8 expression in human control and AD brains. Nedd8 staining was present in the nucleus in control hippocampal neurons, but it was localized in the cytoplasm in AD hippocampal neurons. Frozen sections were stained with rabbit anti-nedd8 (Zymed).

Fig. 4

Neddylation regulates APP functions in NPC development. A. The cleavage of APP by the a-secretase generates sAPPa that favors NPC self-renewal. B. Production of Aβ40 and Aβ42 by the β- and γ-secretase cleavage promotes NPC differentiation. Aβ40 promotes neurogenesis whereas Aβ42 promotes gliagenesis [117]. BP1-activated neddylation of APP supports the non-amyloidogenic processing of APP and downregulates AICD. Both of these effects may promote neuronal differentiation. Blue, APP, sAPPa, or AICD; red, Aβ; purple, lysine residues in AICD; Black, unknown receptors or ligand.