Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

Sullivan, Courtney R.; Koene, Rachael; Hasselfeld, Kathryn; O’Donovan, Sinead M.; Ramsey, Amy J.; McCullumsmith, Robert E.

doi:10.1038/s41380-018-0035-3

Cited by 51 publications

(47 citation statements)

References 74 publications

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“…In addition, Ingenuity Pathway Analysis TM demonstrated significant enrichment of molecular pathways, e.g., glycolysis I, TCA (tricarboxylic acid) cycle II, and dopamine-DARPP32 feedback in cAMP signaling, for the downregulated genes (P < 0.05) ( Fig 8D and Appendix Table S14). This evidence is consistent with energy metabolism dysfunction (Zuccoli et al, 2017;Sullivan et al, 2019) and the involvement of deficits in DARP32 systems in the pathogenesis of schizophrenia (Kunii et al, 2014;Wang et al, 2017;Zuccoli et al, 2017).…”

Section: Frontal Cortex Lymphocytesupporting

confidence: 82%

Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology

et al. 2019

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Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as‐yet‐unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H2S)/polysulfide‐producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst‐deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst‐transgenic (Tg) mice showed deteriorated PPI, suggesting that “sulfide stress” may be linked to PPI impairment. Analysis of human samples demonstrated that the H2S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst‐Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H2S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H2S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H2S/polysulfides production.

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Section: Frontal Cortex Lymphocytesupporting

confidence: 82%

Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology

et al. 2019

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“…[ 46 ] Consistently, a decrease in the expression of multiple metabolic genes was found with laser‐capture microdissection in pyramidal neurons of DLPFC in SCZ. [ 88 ] In the substantia nigra, which is predominantly composed of dopaminergic neurons, the highest levels of mtDNA deletions are found compared to other brain regions such as the DLPFC, hippocampus, nucleus accumbens, orbitofrontal cortex, or thalamus. [ 89,90 ] Unfortunately, no functional outcomes such as mitochondrial gene expression dysregulation or mitochondrial dysfunction were analyzed in these studies.…”

Section: Mitochondria Dysfunction In People With Schizophreniamentioning

confidence: 99%

Mitochondrial Dysfunction in Schizophrenia

Chung

2020

BioEssays

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Schizophrenia (SCZ) is a severe neurodevelopmental disorder affecting 1% of populations worldwide with a grave disability and socioeconomic burden. Current antipsychotic medications are effective treatments for positive symptoms, but poorly address negative symptoms and cognitive symptoms, warranting the development of better treatment options. Further understanding of SCZ pathogenesis is critical in these endeavors. Accumulating evidence has pointed to the role of mitochondria and metabolic dysregulation in SCZ pathogenesis. This review critically summarizes recent studies associating a compromised mitochondrial function with people with SCZ, including postmortem studies, imaging studies, genetic studies, and induced pluripotent stem cell studies. This review also discusses animal models with mitochondrial dysfunction resulting in SCZ-relevant neurobehavioral abnormalities, as well as restoration of mitochondrial function as potential therapeutic targets. Further understanding of mitochondrial dysfunction in SCZ may open the door to develop novel therapeutic strategies that can address the symptoms that cannot be adequately addressed by current antipsychotics alone.

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“…34 Two datasets examined transcript levels in laser capture microdissected pyramidal neurons from superficial (lamina II-III) or deep (lamina V-VI) cortical layers of the DLPFC. 35 The data were processed and analyzed using various R packages for differential expression analysis such as edgeR, DESeq2, and limma. [36][37][38] The datasets are then aggregated and uniquely titled for processing.…”

Section: Bioinformatic Analysismentioning

confidence: 99%

Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

Pinner

Mueller

Alganem

et al. 2019

Preprint

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The pathophysiology of schizophrenia includes altered neurotransmission, dysregulated intracellular signaling pathway activity, and abnormal dendritic morphology that contribute to deficits of synaptic plasticity in the disorder. These processes all require dynamic protein-protein interactions at cell membranes. Lipid modifications target proteins to membranes by increasing substrate hydrophobicity by the addition of a fatty acid or isoprenyl moiety, and recent evidence suggests that dysregulated posttranslational lipid modifications may play a role in multiple neuropsychiatric disorders including schizophrenia. Consistent with these emerging findings, we have recently reported decreased protein S-palmitoylation in schizophrenia. Protein prenylation is a lipid modification that occurs upstream of Spalmitoylation on many protein substrates, facilitating membrane localization and activity of key intracellular signaling proteins. Accordingly, we hypothesized that in addition to palmitoylation, protein prenylation may be abnormal in schizophrenia. To test this, we assayed protein expression of the five prenyltransferase subunits (FNTA, FNTB, PGGT1B, RABGGTA, and RABGGTB) in postmortem dorsolateral prefrontal cortex from patients with schizophrenia and paired comparison subjects (N = 13 pairs). We found decreased levels of FNTA (14%), PGGT1B (13%), and RABGGTB (8%) in schizophrenia. To determine if upstream or downstream factors may be driving these changes, we also assayed protein expression of the isoprenoid synthases FDPS and GGPS1, and prenylation-dependent processing enzymes REC and ICMT. We found these upstream and downstream enzymes to have normal protein expression. To rule out effects from chronic antipsychotic treatment, we assayed FNTA, PGGT1B and RABGGTB in cortex from rats treated long-term with haloperidol decanoate, and found no change in the expression of these proteins. Given the role prenylation plays in localization of key signaling proteins found at the synapse, these data offer a potential mechanism underlying abnormal protein-protein interactions and protein localization in schizophrenia.

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Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

Cited by 51 publications

References 74 publications

Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology

Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology

Mitochondrial Dysfunction in Schizophrenia

Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

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