Ubiquilin-1 Protects Cells from Oxidative Stress and Ischemic Stroke Caused Tissue Injury in Mice

Li, Yanying; Lü, Lei; Hettinger, Casey L.; Dong, Gaofeng; Zhang, Dong; Rezvani, Khosrow; Wang, Xuejun; Wang, Hongmin

doi:10.1523/jneurosci.3541-13.2014

Cited by 66 publications

(85 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ubiquilin-1 is a ubiquitin-like protein also known as UBQLN1. It mediates degradation of misfolded proteins and contributes to brain protection from oxidative stress and ischemic stroke [26]. Surprisingly, ubiquitin C-terminal hydrolase L1, which removes ubiquitin and prevents protein degradation, was also overexpressed.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protein Profile and Morphological Alterations in Penumbra after Focal Photothrombotic Infarction in the Rat Cerebral Cortex

et al. 2016

View full text Add to dashboard Cite

After ischemic stroke, cell damage propagates from infarct core to surrounding tissues (penumbra). To reveal proteins involved in neurodegeneration and neuroprotection in penumbra, we studied protein expression changes in 2-mm ring around the core of photothrombotic infarct induced in the rat brain cortex by local laser irradiation after administration of Bengal Rose. The ultrastructural study showed edema and degeneration of neurons, glia, and capillaries. Morphological changes gradually decreased across the penumbra. Using the antibody microarrays, we studied changes in expression of >200 neuronal proteins in penumbra 4 or 24 h after focal photothrombotic infarct. Diverse cellular subsystems were involved in the penumbra tissue response: signal transduction pathways such as protein kinase Bα/GSK-3, protein kinase C and its β1 and β2 isoforms, Wnt/β-catenin (axin1, GSK-3, FRAT1), Notch/NUMB, DYRK1A, TDP43; mitochondria quality control (Pink1, parkin, HtrA2); ubiquitin-mediated proteolysis (ubiquilin-1, UCHL1); axon outgrowth and guidance (NAV-3, CRMP2, PKCβ2); vesicular trafficking (syntaxin-8, TMP21, Munc-18-3, synip, ALS2, VILIP1, syntaxin, synaptophysin, synaptotagmin); biosynthesis of neuromediators (tryptophan hydroxylase, monoamine oxidase B, glutamate decarboxylase, tyrosine hydroxylase, DOPA decarboxylase, dopamine transporter); intercellular interactions (N-cadherin, PMP22); cytoskeleton (neurofilament 68, neurofilament-M, doublecortin); and other proteins (LRP1, prion protein, β-amyloid). These proteins are involved in neurodegeneration or neuroprotection. Such changes were most expressed 4 h after photothrombotic impact. Immunohistochemical and Western blot studies of expression of monoamine oxidase B, UCHL1, DYRK1A, and Munc-18-3 confirmed the proteomic data. These data provide the integral view on the penumbra response to photothrombotic infarct. Some of these proteins can be potential targets for ischemic stroke therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

“…β-Amyloid is produced from amyloid precursor protein (APP) by TMP21, a member of the presenilin complex [42]. The observed accumulation of β-amyloid peptide (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) in penumbra could be also neurotoxic.…”

Section: Discussionmentioning

confidence: 99%

Protein Profile and Morphological Alterations in Penumbra after Focal Photothrombotic Infarction in the Rat Cerebral Cortex

et al. 2016

View full text Add to dashboard Cite

show abstract

“…To generate the LV-Ublqn, we replaced the cDNA encoding GFP in the pLenti-CMV-GFP plasmid (Campeau et al 2009) with a full length mouse Ubqln cDNA sequence (Liu et al 2014b). The four different mouse LV-Ubqln-shRNAs and the scramble control were purchased from OriGene (Rockville, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Our previous studies have revealed that ubiquilin1 (Ubqln) interacts with misfolded proteins and selectively enhances their degradation (Wang and Monteiro 2007). Our recent results suggest that Ubqln is a potential therapeutic target for ischemic stroke, as overexpression (OE) of Ubqln protects cells against oxidative stress and ischemia/reperfusion (I/R)-caused brain injury but knockout (KO) of the gene shows the opposite results (Liu et al 2014b). In these studies, however, alteration of Ubqln expression occurs prior to ischemic insults.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Proteostasis in Post-ischemic Stroke Mouse Brains by Ubiquilin-1 Promotes Functional Recovery

Qiao

Wang

2016

Cell Mol Neurobiol

View full text Add to dashboard Cite

Stroke is pathologically associated with oxidative stress, protein damage, and neuronal loss. We previously reported that overexpression of a ubiquitin-like protein, ubiquilin-1 (Ubqln), protects neurons against ischemia-caused brain injury, while knockout of the gene exacerbates cerebral ischemia-caused neuronal damage and delays functional recovery. Although these observations indicate that Ubqln is a potential therapeutic target, transgenic manipulation-caused overexpression of Ubqln occurs before the event of ischemic stroke, and it remains unknown whether delayed Ubqln overexpression in post-ischemic brains within a clinically relevant time frame is still beneficial. To address this question, we generated lentiviruses either overexpressing or knocking down mouse Ubqln, and treated post-ischemic stroke mice 6 h following the middle cerebral artery occlusion with the lentiviruses before animal behaviors were evaluated at day 1, 3, 5, and 7. Our data indicate that post-ischemic overexpression of Ubqln significantly promoted functional recovery, whereas post-ischemic downregulation of Ubqln expression delays functional recovery. To further understand the mechanisms underlying how Ubqln functions, we also isolated protein aggregates from the brains of wild-type mice or the mice overexpressing Ubqln following ischemia/reperfusion. Western blot analysis indicates that overexpression of Ubqln significantly reduced the accumulation of protein aggregates. These observations not only suggest that Ubqln is a useful candidate for therapeutic intervention for ischemic stroke but also highlight the significance of proteostasis in functional recovery following stroke.

show abstract

“…Transgenic mice globally over-expressing ubiquilin-1 exhibit resistance to oxidative stress and ischemia/reperfusion injuries in the CNS (Liu et al, 2014), which parallels the resistance of cd47 null mice to cerebral ischemia (Jin et al, 2009). CD47 and ubiquilin-1 also share roles in regulation of cytoplasmic calcium levels.…”

Section: Proximal Signalingmentioning

confidence: 99%

CD47 signaling pathways controlling cellular differentiation and responses to stress

Soto-Pantoja

Kaur

Roberts

2015

Critical Reviews in Biochemistry and Molecular Biology

156

166

View full text Add to dashboard Cite

CD47 is a widely expressed integral membrane protein that serves as the counter-receptor for the inhibitory phagocyte receptor signal-regulatory protein-α (SIRPα) and as a signaling receptor for the secreted matricellular protein thrombospondin-1. Recent studies employing mice and somatic cells lacking CD47 have revealed important pathophysiological functions of CD47 in cardiovascular homeostasis, immune regulation, resistance of cells and tissues to stress, and chronic diseases of aging including cancer. With the emergence of experimental therapeutics targeting CD47, a more thorough understanding of CD47 signal transduction is essential. CD47 lacks a substantial cytoplasmic signaling domain, but several cytoplasmic binding partners have been identified, and lateral interactions of CD47 with other membrane receptors play important roles in mediating signaling resulting from the binding of thrombospondin-1. This review addresses recent advances in identifying the lateral binding partners, signal transduction pathways, and downstream transcription networks regulated through CD47 in specific cell lineages. Major pathways regulated by CD47 signaling include calcium homeostasis, cyclic nucleotide signaling, nitric oxide and hydrogen sulfide biosynthesis and signaling, and stem cell transcription factors. These pathways and other undefined proximal mediators of CD47 signaling regulate cell death and protective autophagy responses, mitochondrial biogenesis, cell adhesion and motility, and stem cell self-renewal. Although thrombospondin-1 is the best characterized agonist of CD47, the potential roles of other members of the thrombospondin family, SIRPα and SIRPγ binding, and homotypic CD47 interactions as agonists or antagonists of signaling through CD47 should also be considered.

show abstract

Ubiquilin-1 Protects Cells from Oxidative Stress and Ischemic Stroke Caused Tissue Injury in Mice

Cited by 66 publications

References 39 publications

Protein Profile and Morphological Alterations in Penumbra after Focal Photothrombotic Infarction in the Rat Cerebral Cortex

Protein Profile and Morphological Alterations in Penumbra after Focal Photothrombotic Infarction in the Rat Cerebral Cortex

Enhanced Proteostasis in Post-ischemic Stroke Mouse Brains by Ubiquilin-1 Promotes Functional Recovery

CD47 signaling pathways controlling cellular differentiation and responses to stress

Contact Info

Product

Resources

About