Signature changes in ubiquilin expression in the R6/2 mouse model of Huntington’s disease

Safren, Nathaniel; Chang, Lydia; Dziki, Kristina M.; Monteiro, Mervyn J.

doi:10.1016/j.brainres.2014.12.008

Cited by 16 publications

(14 citation statements)

References 45 publications

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“…This protective effect is consistent with previous reports that increasing the expression of UBQLN2 or its family members protects against the toxicity of a variety of neurodegenerationrelated proteins, including amyloid-β, polyglutamine repeats, and TDP-43 (80)(81)(82). Collectively, the present study results reveal that UBQLN2 directly regulates the early stages of SG formation and suggest that it has a critical cytoprotective role at the junction between protein and RNA homeostasis, both of which underlie neurodegenerative diseases.…”

Section: Discussionsupporting

confidence: 92%

Ubiquilin 2 modulates ALS/FTD-linked FUS–RNA complex dynamics and stress granule formation

Alexander

Niaki

Zhang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

113

105

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The ubiquitin-like protein ubiquilin 2 (UBQLN2) has been genetically and pathologically linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but its normal cellular functions are not well understood. In a search for UBQLN2-interacting proteins, we found an enrichment of stress granule (SG) components, including ALS/FTD-linked heterogeneous ribonucleoprotein fused in sarcoma (FUS). Through the use of an optimized SG detection method, we observed UBQLN2 and its interactors at SGs. A low complexity, Sti1-like repeat region in UBQLN2 was sufficient for its localization to SGs. Functionally, UBQLN2 negatively regulated SG formation. UBQLN2 increased the dynamics of FUS–RNA interaction and promoted the fluidity of FUS–RNA complexes at a single-molecule level. This solubilizing effect corresponded to a dispersal of FUS liquid droplets in vitro and a suppression of FUS SG formation in cells. ALS-linked mutations in UBQLN2 reduced its association with FUS and impaired its function in regulating FUS–RNA complex dynamics and SG formation. These results reveal a previously unrecognized role for UBQLN2 in regulating the early stages of liquid–liquid phase separation by directly modulating the fluidity of protein–RNA complexes and the dynamics of SG formation.

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Section: Discussionsupporting

confidence: 92%

Ubiquilin 2 modulates ALS/FTD-linked FUS–RNA complex dynamics and stress granule formation

Alexander

Niaki

Zhang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

113

105

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“…UBQLN2 is one of four homologous UBQLN proteins expressed in humans. Of the four isoforms, UBQLN3 is only expressed in the testis, while the remaining isoforms are differentially expressed throughout the body (7)(8)(9)(10)(11). The proteins are all about 600-aa long and contain highly homologous ubiquitin-like (UBL) and ubiquitinassociated (UBA) domains at their N and C termini, respectively.…”

mentioning

confidence: 99%

ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function

Cai

Greenslade

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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Mutations inUBQLN2cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerations. However, the mechanism by which the UBQLN2 mutations cause disease remains unclear. Alterations in proteins involved in autophagy are prominent in neuronal tissue of human ALSUBQLN2patients and in a transgenic P497S UBQLN2 mouse model of ALS/FTD, suggesting a pathogenic link. Here, we show UBQLN2 functions in autophagy and that ALS/FTD mutant proteins compromise this function. Inactivation of UBQLN2 expression in HeLa cells reduced autophagic flux and autophagosome acidification. The defect in acidification was rescued by reexpression of wild type (WT) UBQLN2 but not by any of the five different UBQLN2 ALS/FTD mutants tested. Proteomic analysis and immunoblot studies revealed P497S mutant mice and UBQLN2 knockout HeLa and NSC34 cells have reduced expression of ATP6v1g1, a critical subunit of the vacuolar ATPase (V-ATPase) pump. Knockout of UBQLN2 expression in HeLa cells decreased turnover of ATP6v1g1, while overexpression of WT UBQLN2 increased biogenesis of ATP6v1g1 compared with P497S mutant UBQLN2 protein. In vitro interaction studies showed that ATP6v1g1 binds more strongly to WT UBQLN2 than to ALS/FTD mutant UBQLN2 proteins. Intriguingly, overexpression of ATP6v1g1 in UBQLN2 knockout HeLa cells increased autophagosome acidification, suggesting a therapeutic approach to overcome the acidification defect. Taken together, our findings suggest that UBQLN2 mutations drive pathogenesis through a dominant-negative loss-of-function mechanism in autophagy and that UBQLN2 functions as an important regulator of the expression and stability of ATP6v1g1. These findings may have important implications for devising therapies to treatUBQLN2-linked ALS/FTD.

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“…In a study by Stieren et al, reduction of ubiquilin-1 activity, led to the production of APP fragments, along with neuronal cell death (Stieren et al, 2011). Ubiquilin-1 seems to also contribute to the pathogenesis of other neurodegenerative disorders (Safren et al, 2015).…”

Section: Ubiquitin-proteasome System and Ubiquilin-1mentioning

confidence: 98%

Targeting Ubiquitin-Proteasome Pathway by Natural Products: Novel Therapeutic Strategy for Treatment of Neurodegenerative Diseases

et al. 2020

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Polyphenols can act as proteasome-inhibitors or may modulate the proteasome activity, thereby improving neurodegenerative disorders by means of accumulation of ubiquitinated proteins, suppression of neuronal apoptosis, reduction of neurotoxicity, and improvement of synaptic plasticity and transmission. HIGHLIGHTS • Aberrant accumulation of intracellular ubiquitin-positive inclusions associated to neurodegenerative disorders. • Polyphenols, can act as proteasome-inhibitors or may modulate the proteasome activity. • Polyphenols can manage neurodegenerative impairments by targeting the ubiquitin-proteasome system (UPS). • Polyphenols exert UPS inhibitory activity, resulting in the accumulation of ubiquitinated proteins, suppression of neuronal apoptosis, reduction of neurotoxicity, and improvement of synaptic plasticity and transmission.

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Signature changes in ubiquilin expression in the R6/2 mouse model of Huntington’s disease

Cited by 16 publications

References 45 publications

Ubiquilin 2 modulates ALS/FTD-linked FUS–RNA complex dynamics and stress granule formation

Ubiquilin 2 modulates ALS/FTD-linked FUS–RNA complex dynamics and stress granule formation

ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function

Targeting Ubiquitin-Proteasome Pathway by Natural Products: Novel Therapeutic Strategy for Treatment of Neurodegenerative Diseases

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