Alterations of ubiquitin related proteins in the pathology and development of schizophrenia: Evidence from human and animal studies

Andrews, Jessica L.; Goodfellow, Frederic J.; Matosin, Natalie; Snelling, Mollie; Newell, Kelly A.; Huang, Xu‐Feng; Fernandez, Francesca

doi:10.1016/j.jpsychires.2017.01.009

Cited by 14 publications

(10 citation statements)

References 71 publications

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“…Although we did not measure deubiquitination activity in the current study, three previous gene expression studies have implicated down-regulated expression of deubiquitinating enzymes in postmortem hippocampal neurons 7 and prefrontal cortex tissue 9,10 from those with schizophrenia. The deubiquitinating enzyme, UCHL1 , was reported as down-regulated across these studies and in a phencyclidine rat model of schizophrenia 45,46 . However, brain lysates from Gracile axonal dystrophy mice, which lack UCHL1 , do not show an accumulation of ubiquitinated proteins 47 , indicating a limited role, if any, in the elevation of ubiquitinated proteins in the current study.…”

Section: Discussionmentioning

confidence: 86%

Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia

Bousman

Luza

Mancuso

et al. 2019

Sci Rep

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Dysregulation of the ubiquitin proteasome system (UPS) has been linked to schizophrenia but it is not clear if this dysregulation is detectable in both brain and blood. We examined free mono-ubiquitin, ubiquitinated proteins, catalytic ubiquitination, and proteasome activities in frozen postmortem OFC tissue from 76 (38 schizophrenia, 38 control) matched individuals, as well as erythrocytes from 181 living participants, who comprised 30 individuals with recent onset schizophrenia (mean illness duration = 1 year), 63 individuals with ‘treatment-resistant’ schizophrenia (mean illness duration = 17 years), and 88 age-matched participants without major psychiatric illness. Ubiquitinated protein levels were elevated in postmortem OFC in schizophrenia compared to controls (p = <0.001, AUC = 74.2%). Similarly, individuals with ‘treatment-resistant’ schizophrenia had higher levels of ubiquitinated proteins in erythrocytes compared to those with recent onset schizophrenia (p < 0.001, AUC = 65.5%) and controls (p < 0.001, AUC = 69.4%). The results could not be better explained by changes in proteasome activity, demographic, medication, or tissue factors. Our results suggest that ubiquitinated protein formation may be abnormal in both the brain and erythrocytes of those with schizophrenia, particularly in the later stages or specific sub-groups of the illness. A derangement in protein ubiquitination may be linked to pathogenesis or neurotoxicity in schizophrenia, and its manifestation in the blood may have prognostic utility.

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Section: Discussionmentioning

confidence: 86%

Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia

Bousman

Luza

Mancuso

et al. 2019

Sci Rep

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“…Several changes in the UPS have been related to schizophrenia through studies involving postmortem brains of patients. These studies have found changes in the levels of ubiquitinated proteins 41,42 , the expression of ubiquitinating, deubiquitinating and conjugating enzymes [42][43][44][45][46][47] and a reduction in free ubiquitin levels 47 .…”

Section: Resultsmentioning

confidence: 99%

Ubiquitin–proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia

Seabra

Almeida

Reis‐de‐Oliveira

et al. 2020

Sci Rep

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Schizophrenia is a chronic, severe and disabling psychiatric disorder, whose treatment is based on psychosocial interventions and the use of antipsychotic drugs. While the effects of these drugs are well elucidated in neuronal cells, they are still not so clear in oligodendrocytes, which play a vital role in schizophrenia. Thus, we aimed to characterize biochemical profiles by proteomic analyses of human oligodendrocytes (MO3.13) which were matured using a protocol we developed and treated with either haloperidol (a typical antipsychotic), clozapine (an atypical antipsychotic) or a clozapine + d-serine co-treatment, which has emerged lately as an alternative type of treatment. this was accomplished by employing shotgun proteomics, using nanoeSi-Lc-MS/MS labelfree quantitation. Proteomic analysis revealed biochemical pathways commonly affected by all tested antipsychotics were mainly associated to ubiquitination, proteasome degradation, lipid metabolism and DNA damage repair. Clozapine and haloperidol treatments also affected proteins involved with the actin cytoskeleton and with EIF2 signaling. In turn, metabolic processes, especially the metabolism of nitrogenous compounds, were a predominant target of modulation of clozapine + d-serine treatment. in this context, we seek to contribute to the understanding of the biochemical and molecular mechanisms involved in the action of antipsychotics on oligodendrocytes, along with their possible implications in schizophrenia. Abbreviations ACC Anterior cingulate cortex ACN Acetonitrile ACTB Beta-actin CNPase 2′,3′-Cyclic-nucleotide-3-phosphodiesterase COPS8 COP9 signalosome complex subunit 8 DIA Data-independent acquisition DLPFC Dorsolateral prefrontal cortex DMEM Dulbecco's modified eagle medium DTT Dithiothreitol eIF2 Eukaryotic initiation factor-2

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“…One of them is regulation of DUBs that convert Ub conjugates into their monomeric free forms, and consequently increase the levels of Ub pool [ 87 ]. UCHL1, a DUB enzyme for Rps27a (see previous paragraph), dysfunction is associated with a variety of NDDs, including AD [ 88 , 89 ], PD [ 90 – 92 ], HD [ 93 , 94 ] and SD [ 95 ]. The other way is regulation of gene expression of monomeric Ub-ribosomal fusion genes as well as polyubiquitin genes.…”

Section: Discussionmentioning

confidence: 99%

Rps27a might act as a controller of microglia activation in triggering neurodegenerative diseases

et al. 2020

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Neurodegenerative diseases (NDDs) are increasing serious menaces to human health in the recent years. Despite exhibiting different clinical phenotypes and selective neuronal loss, there are certain common features in these disorders, suggesting the presence of commonly dysregulated pathways. Identifying causal genes and dysregulated pathways can be helpful in providing effective treatment in these diseases. Interestingly, in spite of the considerable researches on NDDs, to the best of our knowledge, no dysregulated genes and/or pathways were reported in common across all the major NDDs so far. In this study, for the first time, we have applied the three-way interaction model, as an approach to unravel sophisticated gene interactions, to trace switch genes and significant pathways that are involved in six major NDDs. Subsequently, a gene regulatory network was constructed to investigate the regulatory communication of statistically significant triplets. Finally, KEGG pathway enrichment analysis was applied to find possible common pathways. Because of the central role of neuroinflammation and immune system responses in both pathogenic and protective mechanisms in the NDDs, we focused on immune genes in this study. Our results suggest that "cytokine-cytokine receptor interaction" pathway is enriched in all of the studied NDDs, while "osteoclast differentiation" and "natural killer cell mediated cytotoxicity" pathways are enriched in five of the NDDs each. The results of this study indicate that three pathways that include "osteoclast differentiation", "natural killer cell mediated cytotoxicity" and "cytokine-cytokine receptor interaction" are common in five, five and six NDDs, respectively. Additionally, our analysis showed that Rps27a as a switch gene, together with the gene pair { Il-18 , Cx3cl1 } form a statistically significant and biologically relevant triplet in the major NDDs. More specifically, we suggested that Cx3cl1 might act as a potential upstream regulator of Il-18 in microglia activation, and in turn, might be controlled with Rps27a in triggering NDDs.

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Alterations of ubiquitin related proteins in the pathology and development of schizophrenia: Evidence from human and animal studies

Cited by 14 publications

References 71 publications

Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia

Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia

Ubiquitin–proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia

Rps27a might act as a controller of microglia activation in triggering neurodegenerative diseases

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