Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia

Martins-de-Souza, Daniel; Gattaz, Wagner F.; Schmitt, Andrea; Maccarrone, Giuseppina; Hunyadi‐Gulyás, Éva; Eberlin, Marcos N.; Souza, Gustavo H.M.F.; Marangoni, Sérgio; Novello, José Camillo; Turck, Christoph W.; Dias-Neto, Emmanuel

doi:10.1016/j.jpsychires.2008.11.006

Cited by 166 publications

(123 citation statements)

References 73 publications

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“…Alternatively, the relative decrease in 19S proteasome complexes we found may be the result of the cell funneling its resources into less energetically demanding degradation mechanisms, such as lysosomal degradation, which is targeted by K63-linked polyubiquitination (MacGurn et al, 2012), or degradation by other proteasome types, which require neither ubiquitination nor ATP (Voges et al, 1999). BDNF and myelin basic protein, two proteins that have been consistently shown to be decreased in schizophrenia (Martins-de-Souza et al, 2009;Jindal et al, 2010;Green et al, 2011;Zhang et al, 2012) are examples of proteins not degraded through ubiquitin-dependent proteasome activity. BDNF is degraded in the lysosome (Evans et al, 2011) and myelin basic protein can be degraded by metalloproteinases and the proteasome in an ubiquitin-independent manner (Chandler et al, 1995;Belogurov et al, 2015).…”

Section: Discussionmentioning

confidence: 91%

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

Scott

Rubio

Haroutunian

et al. 2015

Neuropsychopharmacol

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The ubiquitin proteasome system (UPS) is a major regulator of protein processing, trafficking, and degradation. While protein ubiquitination is utilized for many cellular processes, one major function of this system is to target proteins to the proteasome for degradation. In schizophrenia, studies have found UPS transcript abnormalities in both blood and brain, and we have previously reported decreased protein expression of ubiquitin-associated proteins in brain. To test whether the proteasome is similarly dysregulated, we measured the protein expression of proteasome catalytic subunits as well as essential subunits from proteasome regulatory complexes in 14 pair-matched schizophrenia and comparison subjects in superior temporal cortex. We found decreased expression of Rpt1, Rpt3, and Rpt6, subunits of the 19S regulatory particle essential for ubiquitin-dependent degradation by the proteasome. Additionally, the α subunit of the 11S αβ regulatory particle, which enhances proteasomal degradation of small peptides and unfolded proteins, was also decreased. Haloperidol-treated rats did not have altered expression of these subunits, suggesting the changes we observed in schizophrenia are likely not due to chronic antipsychotic treatment. Interestingly, expression of the catalytic subunits of both the standard and immunoproteasome were unchanged, suggesting the abnormalities we observed may be specific to the complexed state of the proteasome. Aging has significant effects on the proteasome, and several subunits (20S β2, Rpn10, Rpn13, 11Sβ, and 11Sγ) were significantly correlated with subject age. These data provide further evidence of dysfunction of the ubiquitin-proteasome system in schizophrenia, and suggest that altered proteasome activity may be associated with the pathophysiology of this illness.

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Section: Discussionmentioning

confidence: 91%

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

Scott

Rubio

Haroutunian

et al. 2015

Neuropsychopharmacol

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“…However, schizophrenia has been repeatedly associated with an increased predisposition to metabolic dysfunction and type II diabetes in medication-naïve individuals (50). Studies suggest glycolytic dysfunction (51,52), mitochondrial failure, and oxidative stress (53) may be innate metabolic pathologies in schizophrenia and bipolar disorder.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3

MacIntyre

Machell

et al. 2011

Mol Psychiatry

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The basic helix-loop-helix PAS (Per, Arnt, Sim) domain transcription factor gene NPAS3 is a replicated genetic risk factor for psychiatric disorders. A knockout (KO) mouse model exhibits behavioral and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 etiopathology, we combined immunofluorescent, transcriptomic and metabonomic approaches. Intense Npas3 immunoreactivity was observed in the hippocampal subgranular zone-the site of adult neurogenesis-but was restricted to maturing, rather than proliferating, neuronal precursor cells. Microarray analysis of a HEK293 cell line over-expressing NPAS3 showed that transcriptional targets varied according to circadian rhythm context and C-terminal deletion. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was just one of many NPAS3 target genes also regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental function. The parallel repression of multiple glycolysis genes by NPAS3 reveals a second role in the regulation of glucose metabolism. Comparison of wild-type and Npas3 KO metabolite composition using high-resolution mass spectrometry confirmed these transcriptional findings. KO brain tissue contained significantly altered levels of NAD(+), glycolysis metabolites (such as dihydroxyacetone phosphate and fructose-1,6-bisphosphate), pentose phosphate pathway components and Kreb's cycle intermediates (succinate and α-ketoglutarate). The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of mental illness etiology, and may provide a mechanism for innate and medication-induced susceptibility to diabetes commonly reported in psychiatric patients

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“…37 Usingproteomicmethods, it is possible to assess global differential protein expression between disease and control states and to obtain novel insights into disease (for reviews, see the articles by English etal, 38 Görgetal, 39 andTannuandHemby 40 ).Proteomicstudies of postmortem brain tissue from subjects with schizophrenia and from subjects with bipolar disorder have focused largely on the dorsolateral prefrontal cortex [41][42][43][44][45][46][47][48][49] and the anterior cingulate cortex. [50][51][52][53] They have demonstrated alterations in cytoskeletal, synaptic, metabolic, and mitochondrial proteins.…”

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confidence: 99%

Common Proteomic Changes in the Hippocampus in Schizophrenia and Bipolar Disorder and Particular Evidence for Involvement of Cornu Ammonis Regions 2 and 3

Föcking

Dicker²,

English³

et al. 2011

Arch Gen Psychiatry

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Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia

Cited by 166 publications

References 73 publications

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3

Common Proteomic Changes in the Hippocampus in Schizophrenia and Bipolar Disorder and Particular Evidence for Involvement of Cornu Ammonis Regions 2 and 3

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