Ubiquilin 1 Modulates Amyloid Precursor Protein Trafficking and Aβ Secretion

• Published in: The Journal of biological chemistry 2006-10, Vol.281 (43), p.32240-32253
• Main Authors: Hiltunen, Mikko, Lu, Alice, Thomas, Anne V., Romano, Donna M., Kim, Minji, Jones, Phill B., Xie, Zhongcong, Kounnas, Maria Z., Wagner, Steven L., Berezovska, Oksana, Hyman, Bradley T., Tesco, Giuseppina, Bertram, Lars, Tanzi, Rudolph E.
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M603106200

Ubiquilin 1 (UBQLN1) is a ubiquitin-like protein, which has been shown to play a central role in regulating the proteasomal degradation of various proteins, including the presenilins. We recently reported that DNA variants in UBQLN1 increase the risk for Alzheimer disease, by influencing expression of this gene in brain. Here we present the first assessment of the effects of UBQLN1 on the metabolism of the amyloid precursor protein (APP). For this purpose, we employed RNA interference to down-regulate UBQLN1 in a variety of neuronal and non-neuronal cell lines. We demonstrate that down-regulation of UBQLN1 accelerates the maturation and intracellular trafficking of APP, while not interfering with α-, β-, or γ-secretase levels or activity. UBQLN1 knockdown increased the ratio of APP mature/immature, increased levels of full-length APP on the cell surface, and enhanced the secretion of sAPP (α- and β-forms). Moreover, UBQLN1 knockdown increased levels of secreted Aβ40 and Aβ42. Finally, employing a fluorescence resonance energy transfer-based assay, we show that UBQLN1 and APP come into close proximity in intact cells, independently of the presence of the presenilins. Collectively, our findings suggest that UBQLN1 may normally serve as a cytoplasmic “gatekeeper” that may control APP trafficking from intracellular compartments to the cell surface. These findings suggest that changes in UBQLN1 steady-state levels affect APP trafficking and processing, thereby influencing the generation of Aβ.