Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction

Tai, Hwan‐Ching; Schuman, Erin M.

doi:10.1038/nrn2499

Cited by 448 publications

(381 citation statements)

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“…The ubiquitin protein system plays an essential role in the regulation of membrane and cellular proteins, and has often been referred to as the "kiss of death" due to its labeling of proteins for degradation by proteases (Petroski, 2008;Tai and Schuman, 2008). The major function of the ubiquitin protein complex is to assure intracellular protein degradation by ubiquitination; a highly complex process involving a set of successive enzymes: E1 (ubiquitin activating enzymes), E2 (ubiquitin-conjugating enzymes), E3…”

Section: Introductionmentioning

confidence: 99%

Investigation of genetic variants in ubiquitin enzyme genes involved in the modulation of neurodevelopmental processes: a role in schizophrenia susceptibility?

Andrews

Fernandez

2014

Genet. Res.

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Despite extensive research during the last few decades, the etiology of schizophrenia remains unclear. Evidence of both genetic and environmental influences in the developmental profile of schizophrenia has grown, and due to the complexity of this disorder, a polygenic aspect has been associated with this neuropsychiatric pathology. Unfortunately, no diagnostic strategies based on biological measurement or genetic testing is currently available for schizophrenia. Gene-expression profiling and recent protein studies have shown a decrease in the expression of ubiquitin pathway proteins in the prefrontal cortex of schizophrenia patients. We have examined single nucleotide polymorphisms (or SNPs) within three genes from the ubiquitin protein system: the ubiquitin conjugating enzyme E2D1 (UBE2D1) gene, the E3 SUMOprotein ligase protein inhibitor of activated STAT 2 (PIAS2) gene, and the E3 ubiquitin ligase F-box and leucine-rich repeat protein 21 (FBXL21) gene, in a Caucasian case-control population for schizophrenia. After Bonferroni correction for multiple testing was applied, no significant associations were reported for any of the tested SNPs. Additional genetic analyses will be necessary to fully explore the role of these three genes in schizophrenia. Regarding the rising interest in ubiquitin-related proteins as a therapeutic target in other pathologies such as cancer, further research into the role of ubiquitin pathways in schizophrenia seems topical and timely. SummaryDespite extensive research during the last decades, the etiology of schizophrenia remains unclear. Evidence of both genetic and environmental influences in the developmental profile of schizophrenia has grown, and due to the complexity of this disorder, a polygenic aspect has been associated with this neuropsychiatric pathology. Unfortunately, no diagnostic strategies based on biological measurement or genetic testing is currently available for schizophrenia. Gene expression profiling and recent protein studies have shown a decrease in the expression of ubiquitin pathway proteins in the prefrontal cortex of schizophrenia patients. We have examined Single Nucleotide Polymorphisms (or SNPs) within three genes from the ubiquitin protein system: the ubiquitin conjugating enzyme E2D1 (UBE2D1) gene, the E3 SUMO-protein ligase protein inhibitor of activated STAT 2 (PIAS2) gene, and the E3 ubiquitin ligase F-box and leucine-rich repeat protein 21 (FBXL21) gene, in a Caucasian case-control population for schizophrenia. After Bonferroni correction for multiple testing was applied, no significant associations were reported for any of the tested SNPs. Additional genetic analyses will be necessary to fully explore the role of these three genes in schizophrenia. Regarding the rising interest of ubiquitin related proteins as a therapeutic target in other pathologies such as cancer, further research into the role of ubiquitin pathways in schizophrenia seem topical and timely.

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Section: Introductionmentioning

confidence: 99%

Investigation of genetic variants in ubiquitin enzyme genes involved in the modulation of neurodevelopmental processes: a role in schizophrenia susceptibility?

Andrews

Fernandez

2014

Genet. Res.

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“…Postsynaptic functions are regulated by finely tuned turnover of the synaptic proteins via the ubiquitin-proteasome system (UPS) (13). We have previously shown that mutant UBQLN2 impairs the UPS in vitro (2).…”

Section: Impairment Of Ubiquitin-proteasome System In Ubqln2 P497h Trmentioning

confidence: 99%

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

Gorrie¹,

Fecto²,

Radzicki

et al. 2014

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

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Mutations in the gene encoding ubiquilin2 (UBQLN2) cause amyotrophic lateral sclerosis (ALS), frontotemporal type of dementia, or both. However, the molecular mechanisms are unknown. Here, we show that ALS/dementia-linked UBQLN2 P497H transgenic mice develop neuronal pathology with ubiquilin2/ubiquitin/p62-positive inclusions in the brain, especially in the hippocampus, recapitulating several key pathological features of dementia observed in human patients with UBQLN2 mutations. A major feature of the ubiquilin2-related pathology in these mice, and reminiscent of human disease, is a dendritic spinopathy with protein aggregation in the dendritic spines and an associated decrease in dendritic spine density and synaptic dysfunction. Finally, we show that the protein inclusions in the dendritic spines are composed of several components of the proteasome machinery, including Ub G76V -GFP, a representative ubiquitinated protein substrate that is accumulated in the transgenic mice. Our data, therefore, directly link impaired protein degradation to inclusion formation that is associated with synaptic dysfunction and cognitive deficits. These data imply a convergent molecular pathway involving synaptic protein recycling that may also be involved in other neurodegenerative disorders, with implications for development of widely applicable rational therapeutics.P rotein aggregates or inclusions with immunoreactivity to ubiquitin represent a common pathological hallmark in a broad range of late-onset neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) (1). However, the molecular mechanisms underlying the formation of these inclusions and their relationship to neuronal dysfunction and degeneration are poorly understood. Mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin2 (UBQLN2), have been recently shown to cause a subset of ALS, FTD-type of dementia, or both (2, 3). Notably, mutations within and in close proximity to the PXX domain of ubiquilin2 appear to have high penetrance as shown in familial cases (2). The distribution of ubiquilin2-positive inclusions in the brain and spinal cord is well correlated with cognitive and motor symptoms of patients with diverse etiology, including chromosome 9 open reading frame 72 (C9ORF72)-linked cases (2, 4). The ubiquilin2-positive inclusions appear to cover a wide range of protein inclusions, including those without TAR DNA binding protein (TDP43) immunoreactivity (2, 4), suggesting a primary role for ubiquilin2 in inclusion formation and neurodegeneration. Therefore, understanding the pathophysiological basis of UBQLN2-linked dementia may provide mechanistic insight into the pathogenesis of neurodegenerative disorders and allow for the design of rational therapies. To this end, we developed and characterized mutant UBQLN2 transgenic mice. ResultsDevelopment of UBQLN2 P497H Transgenic Mice. Human UBQLN2 is an intronless gene. We analyzed the UBQLN2 promoter ...

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“…Further collection of cases with similar characteristics and screening of deletion/mutations of UBE2A in syndromic as well as idiopathic XLMRaffected males, especially those mapped to areas encompassing UBE2A, will be needed to determine the significance and frequency of alterations of this gene as a causative gene for XLMR. Although, several mutations in ubiquitination and proteasome function-related genes, especially in E3 ligase genes, are involved in human neurological disorders, such as UBE3A (Angelman syndrome), PARK2 (recessive juvenile Parkinson disease), UBR1 (Johanson-Blizzard syndrome), NHLRC1 (Lafora's disease) and CUL4B, BRWD3 and HUWE1 (XLMR), 8 UBE2A is the only E2 gene known to be associated with a neurological disease. It will be also necessary to assess whether the mutation or deletion of E2 genes other than UBE2A leads to neurodevelopmental anomalies.…”

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confidence: 99%

Novel deletion at Xq24 including the UBE2A gene in a patient with X-linked mental retardation

et al. 2010

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Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction

Cited by 448 publications

References 145 publications

Investigation of genetic variants in ubiquitin enzyme genes involved in the modulation of neurodevelopmental processes: a role in schizophrenia susceptibility?

Investigation of genetic variants in ubiquitin enzyme genes involved in the modulation of neurodevelopmental processes: a role in schizophrenia susceptibility?

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

Novel deletion at Xq24 including the UBE2A gene in a patient with X-linked mental retardation

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