Disease relevance of UBQLN1

• Moreover, the anti-ubiquilin antibodies robustly stained neurofibrillary tangles and Lewy bodies in AD and Parkinson's disease affected brains, respectively [1].
• Moreover, ubiquilin has the ability to attenuate CHOP induction by hypoxia [2].
• Ubiquilin-1 is a novel HASH-1-complexing protein that regulates levels of neuronal bHLH transcription factors in human neuroblastoma cells [3].
• Here, we report that ubiquilin suppresses polyQ-induced protein aggregation and toxicity in cells and in an animal model of Huntington's disease [4].
• Eight volunteers and two patients with brain tumor were imaged at 3 T. All CSTs were found to lie in a compact area in one part of the PLIC: If the PLIC is divided into four equal quarters from anterior to posterior, the CST was shown to be in the third quarter [5].

Psychiatry related information on UBQLN1

• The gene coding for ubiquilin 1 (UBQLN1) is located near a linkage peak on chromosome 9q22.2 and it also impacts the function of presenilin proteins involved in early-onset Alzheimer's disease (AD) [6].

High impact information on UBQLN1

• The Dsk2 mutation is likely to impair intermediate filament assembly, leading to cytolysis of suprabasal keratinocytes and secondary hyperkeratosis and melanocytosis [7].
• Thus, PLIC-1 inhibits Gi signaling by direct association with Gbetagamma; because it also interacts with CD47, a modulator of integrin function, it likely has a role integrating adhesion and signaling components of cell migration [8].
• PLIC-1 prevented the SDF-1alpha-induced activation of phospholipase C, decreased ligand-induced internalization of SDF-1alpha receptor CXCR4 and inhibited chemotaxis signaled by a transfected Gi-coupled receptor [8].
• PLIC-1, a newly described ubiquitin-related protein, inhibited both Jurkat migration toward SDF-1alpha and A431 wound healing, but the closely related PLIC-2 did not [8].
• The ubiquitin-related protein PLIC-1 regulates heterotrimeric G protein function through association with Gbetagamma [8].

Chemical compound and disease context of UBQLN1

• Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin [4].
• Furthermore, using Western blots, we discovered that GM1 stimulated the expression of Ubiquilin 1 in human neuroblastoma cells and rat cortical neurons while other gangliosides Asialo-GM1 and GD1b did not [9].

Biological context of UBQLN1

• Our haplotype data suggest the presence of additional putative functional variants either in the UBQLN1 gene or nearby genes and provide strong justification for additional work in this region on chromosome 9 [6].
• The purpose of this study was to confirm the reported association in a large case-control sample and to also examine the association of UBQLN1 SNPs with quantitative measures of AD progression, namely age-at-onset (AAO), disease duration and Mini-Mental State Examination (MMSE) score [6].
• Recently, genetic variation in UBQLN1 has been shown to affect the risk of AD in two independent family-based samples [6].
• In contrast, knockdown of ubiquilin-1 and -2 protein expression by RNAi (RNA interference) increased Pen-2 and nicastrin levels [10].
• These studies implicate ubiquilin as an important factor in regulating PS biogenesis and metabolism [10].

Anatomical context of UBQLN1

• For this purpose, we employed RNA interference to down-regulate UBQLN1 in a variety of neuronal and non-neuronal cell lines [11].
• Interestingly, ubiquilin is also up-regulated in response to hypoxia in glial cells with a time course similar to that of PDI induction [2].
• Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death [2].
• In cultured superior cervical ganglion neurons, expression of ubiquilin-1 abolishes nicotine-induced up-regulation of nicotinic acetylcholine receptors but has no effect on the basal level of surface receptors [12].
• PLIC-1 (protein linking IAP to the cytoskeleton) is a ubiquitin-like protein that binds to the ubiquitin-interacting motif (UIM) of the proteasomal subunit S5a [13].

Associations of UBQLN1 with chemical compounds

• Yeast two-hybrid (Y2H) interaction, glutathione S-transferase pull-down experiments, and colocalization of the proteins expressed in vivo, together with coimmunoprecipitation and cell fractionation studies, provide compelling evidence that ubiquilin interacts with both PS1 and PS2 [1].
• Coexpression of ubiquilin-1 and neuronal nicotinic acetylcholine receptors in heterologous cells dramatically reduces the expression of the receptors on the cell surface [12].
• Ubiquilin-1 regulates nicotine-induced up-regulation of neuronal nicotinic acetylcholine receptors [12].
• Using a polyglutamine (polyQ) disease model, we found that both endogenous PLIC-1 and EPS15 localize to perinuclear aggresomes, and that polyQ enhances their in vivo interaction [13].
• We also show that PLIC-1 is upregulated by arsenite-induced protein misfolding [13].

Physical interactions of UBQLN1

• Here, we show that PLIC-1 also binds to the UIM proteins ataxin 3-a deubiquitinating enzyme-HSJ1a-a co-chaperone-and EPS15 (epidermal growth factor substrate 15)-an endocytic protein [13].
• Using glutathione-S-transferase pull-down experiments, we show that the first ubiquitin-interacting motif of Eps15 (UIM1) interacts directly with the UBL domain of ubiquilin, whereas it does not bind to ubiquitinated proteins [14].

Regulatory relationships of UBQLN1

• However, we show that ubiquilin promotes presenilin protein accumulation [1].
• Furthermore, we show that the PS1-ubiquilin 1 interaction can be detected between endogenous proteins in primary neurons in vitro as well as in brain tissue of healthy controls and Alzheimer disease patients, providing evidence of its physiological relevance [15].
• 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 [11].

Other interactions of UBQLN1

• Pulse-labeling experiments indicate that ubiquilin facilitates increased presenilin synthesis without substantially changing presenilin protein half-life [1].
• Interestingly, overexpression of ubiquilin resulted in a decrease in Pen-2 and nicastrin levels, two essential components of the gamma-secretase complex [10].
• We demonstrate that down-regulation of UBQLN1 accelerates the maturation and intracellular trafficking of APP, while not interfering with alpha-, beta-, or gamma-secretase levels or activity [11].
• We show that knockdown of PLIC-1 and EPS15 by RNA interference reduces aggresome formation [13].
• Recently, we have identified a new protein (DA41) which can associate with candidate tumor-suppressor DAN protein [16].

Analytical, diagnostic and therapeutic context of UBQLN1

• Immunohistochemistry of human brain tissue with ubiquilin-specific antibodies revealed prominent staining of neurons [1].
• Sequence analysis revealed that DA41 cDNA is 2,167 nucleotides in length and contains a single open reading frame (ORF) of 582 amino acids (61,945 daltons) [17].
• In a synchronous 3Y1 cell culture, DA41 mRNA was expressed at a low level in quiescent cells; however, its level was significantly increased between the G1 and S phases of the cell cycle [17].
• RESULTS: All seven patients showed decreased diffusion anisotropy and increased diffusion constant in the PLIC, with complete separation from a normal control group, including patients early in the course of the illness [18].

References