Ubiquilin-1 and protein quality control in Alzheimer disease

Abstract

Single nucleotide polymorphisms in the ubiquilin-1 gene may confer risk for late-onset Alzheimer disease (AD). We have shown previously that ubiquilin-1 functions as a molecular chaperone for the amyloid precursor protein (APP) and that protein levels of ubiquilin-1 are decreased in the brains of AD patients. We have recently found that ubiquilin-1 regulates APP trafficking and subsequent secretase processing by stimulating non-degradative ubiquitination of a single lysine residue in the cytosolic domain of APP. Thus, ubiquilin-1 plays a central role in regulating APP biosynthesis, trafficking and ultimately toxicity. As ubiquilin-1 and other ubiquilin family members have now been implicated in the pathogenesis of numerous neurodegenerative diseases, these findings provide mechanistic insights into the central role of ubiquilin proteins in maintaining neuronal proteostasis.

Keywords: :

• Alzheimer disease
• amyloid precursor protein
• molecular chaperone
• trafficking
• ubiquilin-1
• ubiquitination

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Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was supported by NIH grants R21AG031948 (J.M.B. and D.B.) and F30AG030878 (E.S.S.) and funds provided by the Jean C. and William D. Willis Neuroscience Research Endowment (E.S.S.).