Heterozygosity for the proteasomal Psmc1 ATPase is insufficient to cause neuropathology in mouse brain, but causes cell cycle defects in mouse embryonic fibroblasts

Rezvani, Nooshin; Elkharaz, Jamal; Lawler, Karen; Mee, Maureen; Mayer, R. John; Bedford, Lynn

doi:10.1016/j.neulet.2012.05.070

Cited by 7 publications

(7 citation statements)

References 46 publications

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“…However, correlation of proteasome activity measurements and UPS impairment in neurodegenerative diseases is complicated by the fact that it is presently unknown to what extent altered proteasome activity affects the overall flux of degradation of ubiquitylated substrates. Fibroblasts derived from mice with a heterozygous deletion of PSMC1/Rpt2, one of the ATPase subunits of the 19S regulatory particle, develop without obvious defects despite reduced proteasome function (Rezvani et al, 2012). Moreover, proteasome activity can be regulated through expression of individual subunits.…”

Section: Proteasome Activity In Neurodegenerative Diseasesmentioning

confidence: 99%

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

Dantuma

Bott

2014

Front. Mol. Neurosci.

259

208

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The ubiquitin-proteasome system (UPS) has been implicated in neurodegenerative diseases based on the presence of deposits consisting of ubiquitylated proteins in affected neurons. It has been postulated that aggregation-prone proteins associated with these disorders, such as α-synuclein, β-amyloid peptide, and polyglutamine proteins, compromise UPS function, and delay the degradation of other proteasome substrates. Many of these substrates play important regulatory roles in signaling, cell cycle progression, or apoptosis, and their inadvertent stabilization due to an overloaded and improperly functioning UPS may thus be responsible for cellular demise in neurodegeneration. Over the past decade, numerous studies have addressed the UPS dysfunction hypothesis using various model systems and techniques that differ in their readout and sensitivity. While an inhibitory effect of some disease proteins on the UPS has been demonstrated, increasing evidence attests that the UPS remains operative in many disease models, which opens new possibilities for treatment. In this review, we will discuss the paradigm shift that repositioned the UPS from being a prime suspect in the pathophysiology of neurodegeneration to an attractive therapeutic target that can be harnessed to accelerate the clearance of disease-linked proteins.

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Section: Proteasome Activity In Neurodegenerative Diseasesmentioning

confidence: 99%

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

Dantuma

Bott

2014

Front. Mol. Neurosci.

259

208

View full text Add to dashboard Cite

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“…Conditional mouse model displays 26S proteasome depletion and impairment of ubiquitin‐mediated protein degradation resulting in neurodegeneration in the nigrostriatal pathway and forebrain regions (Bedford et al, 2008). While heterozygous knockout mouse brain had no observable differences from that of wild type, an age‐related neuronal ubiquitin immunoreactivity, decreased PSMC1 protein expression, altered assembly of the 26S proteasome and an effect on cell cycle progression was observed (Rezvani et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

14q32.11 microdeletion including CALM1, TTC7B, PSMC1, and RPS6KA5: A new potential cause of developmental and language delay in three unrelated patients

Eno

Graakjær

Svaneby

et al. 2021

American J of Med Genetics Pt A

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Three unrelated patients with similar microdeletions of chromosome 14q32.11 with shared phenotypes including language and developmental delay, and four overlapping genes ‐CALM1, TTC7B, PSMC1, and RPS6KA5 have been presented. All four genes are expressed in the brain and have haploinsufficiency scores, which reflect low tolerance to loss of function variation. An insight on the genes in the overlapping region, which may influence the resulting phenotype has been provided. Given the three patients' similar phenotypes and lack of normal variation in this region, it was suggested that this microdeletion may be associated with developmental and language delay.

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“…TOPORS is associated with the centrosome throughout the cell cycle, localising to mitotic centrioles and to basal bodies of primary cilia, including connecting cilia of photoreceptor cells [ 33 ]. The involvement of P26s4/ PSMC1 in cell cycle defects has been documented in mouse embryonic fibroblasts [ 47 ]. Hence, we were interested in evaluating whether the interaction between TOPORS and P26s4 could occur at the centrosome and/or the basal body of photoreceptor connecting cilium.…”

Section: Discussionmentioning

confidence: 99%

TOPORS, a Dual E3 Ubiquitin and Sumo1 Ligase, Interacts with 26 S Protease Regulatory Subunit 4, Encoded by the PSMC1 Gene

et al. 2016

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The significance of the ubiquitin-proteasome system (UPS) for protein degradation has been highlighted in the context of neurodegenerative diseases, including retinal dystrophies. TOPORS, a dual E3 ubiquitin and SUMO1 ligase, forms a component of the UPS and selected substrates for its enzymatic activities, such as DJ-1/PARK7 and APOBEC2, are important for neuronal as well as retinal homeostasis, respectively. TOPORS is ubiquitously expressed, yet its mutations are only known to result in autosomal dominant retinitis pigmentosa. We performed a yeast two-hybrid (Y2H) screen of a human retinal cDNA library in order to identify interacting protein partners of TOPORS from the retina, and thus begin delineating the putative disease mechanism(s) associated with the retina-specific phenotype resulting from mutations in TOPORS. The screen led to isolation of the 26 S protease regulatory subunit 4 (P26s4/ PSMC1), an ATPase indispensable for correct functioning of UPS-mediated proteostasis. The interaction between endogenous TOPORS and P26s4 proteins was validated by co-immuno-precipitation from mammalian cell extracts and further characterised by immunofluorescent co-localisation studies in cell lines and retinal sections. Findings from hTERT-RPE1 and 661W cells demonstrated that TOPORS and P26s4 co-localise at the centrosome in cultured cells. Immunofluorescent staining of mouse retinae revealed a strong P26s4 reactivity at the interface between retinal pigmented epithelium (RPE) layer and the photoreceptors outer segments (OS). This finding leads us to speculate that P26s4, along with TOPORS, may have a role(s) in RPE phagocytosis, in addition to contributing to the overall photoreceptor and retinal homeostasis via the UPS.

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Heterozygosity for the proteasomal Psmc1 ATPase is insufficient to cause neuropathology in mouse brain, but causes cell cycle defects in mouse embryonic fibroblasts

Cited by 7 publications

References 46 publications

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

14q32.11 microdeletion including CALM1, TTC7B, PSMC1, and RPS6KA5: A new potential cause of developmental and language delay in three unrelated patients

TOPORS, a Dual E3 Ubiquitin and Sumo1 Ligase, Interacts with 26 S Protease Regulatory Subunit 4, Encoded by the PSMC1 Gene

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