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.

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

“…The level of ubiquilin-1 is decreased in both DS and DS/AD compared with their respective age-matched controls and we observed a decreased of K63 poly-Ub levels. Single-nucleotide polymorphisms in the ubiquilin-1 gene are likely a risk factor for late-onset AD (20). Stieren et al demonstrated that overexpression of ubiquilin-1 reduces the Ab 42/40 ratio and prevents APP-induced cellular toxicity (67).…”

Characterization of Dynamic UbR-Proteasome Subcomplexes by In vivo Cross-linking (X) Assisted Bimolecular Tandem Affinity Purification (XBAP) and Label-free Quantitation

“…Among the five ubiquilin proteins, Ubqln1, Ubqln2 and Ubqln4 have been found in all tissues, whereas Ubqln3 and Ubqlnl appear to be enriched in testis (http://www.proteinatlas.org/). In comparison, Ubqln1 and Ubqln2 have the highest levels of expression among all ubiquilin genes in most mouse and human tissues (15), and have been implicated in several neurodegenerative disorders (15,57,58). Therefore, we have selected these two ubiquilins for this work.…”

Extracellular Chaperones in Neuronal Proteinopathies: Protecting and Facilitating Neuronal Function

“…12 Chaperones are constitutively expressed in eukaryotes along with co-chaperones (proteins that facilitate the function of chaperones in protein folding but are not able to do so by themselves only). 8 These chaperones undergo various modifications during cellular stress such as glycosylation, phosphorylation, and 2 …”

“…7 Thus, understanding the proteostasis machinery both within and outside the cells is of importance. A detailed role of heat shock proteins (HSPs), ubiquilin-1, 8 and other intracellular chaperones in proteostasis has been reviewed in detail elsewhere. 9 Here, in this review article, the focus is on the protein quality control at the extracellular space and the abundance of the extracellular chaperones (ECs) in this space on exposure to different stressors such as temperature, pH, oxidised microenvironment, and the shear stress arising from the flow of plasma throughout the body under certain pressure.…”

“…71 For example, SAP localises to elastic microfibrils, arterioles, bronchioles, glomerular and alveolar basement membrane, cardiac and smooth muscles, and almost all forms of amyloid. 68,69 The specific binding of ligands in all these cellular locations involves Ca 2+ -dependent binding to oligosaccharides, 8 …”