Mitochondrial dysfunction in schizophrenia: Pathways, mechanisms and implications

Rajasekaran, Ashwini; Venkatasubramanian, Ganesan; Berk, Michael; Debnath, Monojit

doi:10.1016/j.neubiorev.2014.11.005

Cited by 242 publications

(171 citation statements)

References 186 publications

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“…In agreement with Sivagnanasundaram et al [25] and another two studies (Table 3), we found differential expression of superoxide dismutase [Cu-Zn] (SOD1), which has been observed consistently to be dysregulated in the brain and liver of patients with schizophrenia [22,[54][55][56][57]. Our study and another two studies (Table 3) also found another protein related to oxidative stress, peroxiredoxin-1 (PRDX1), to be downregulated, reinforcing the concept of a reduced response to oxidative stress [58,59].…”

Section: Resultssupporting

confidence: 92%

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Saia-Cereda

Cassoli

Schmitt

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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Schizophrenia is an incurable and debilitating mental disorder that may affect up to 1% of the world population. Morphological, electrophysiological, and neurophysiological studies suggest that the corpus callosum (CC), which is the largest portion of white matter in the human brain and responsible for inter-hemispheric communication, is altered in schizophrenia patients. Here, we employed mass spectrometry-based proteomics to investigate the molecular underpinnings of schizophrenia. Brain tissue samples were collected postmortem from nine schizophrenia patients and seven controls at the University of Heidelberg, Germany. Because the CC has a signaling role, we collected cytoplasmic (soluble) proteins and submitted them to nano-liquid chromatography-mass spectrometry (nano LC-MS/MS). Proteomes were quantified by label-free spectral counting. We identified 5678 unique peptides that corresponded to 1636 proteins belonging to 1512 protein families. Of those proteins, 65 differed significantly in expression: 28 were upregulated and 37 downregulated. Our data increased significantly the knowledge derived from an earlier proteomic study of the CC. Among the differentially expressed proteins are those associated with cell growth and maintenance, such as neurofilaments and tubulins; cell communication and signaling, such as 14-3-3 proteins; and oligodendrocyte function, such as myelin basic protein and myelin-oligodendrocyte glycoprotein. Additionally, 30 of the differentially expressed proteins were found previously in other proteomic studies in postmortem brains; this overlap in findings validates the present study and indicates that these proteins may be markers consistently associated with schizophrenia. Our findings increase the understanding of schizophrenia pathophysiology and may serve as a foundation for further treatment strategies.

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Section: Resultssupporting

confidence: 92%

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Saia-Cereda

Cassoli

Schmitt

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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“…While the 26S proteasome is usually considered more efficient than these other complexes, both uncapped 20S CP and the IP have been shown to be more capable of degrading oxidized proteins (Pickering et al, 2010). Markers of increased oxidative stress such as increased lipid peroxidation, reactive oxygen species, and decreased antioxidant levels have been observed in postmortem brain in schizophrenia (Bošković et al, 2011;Gonzalez-Liencres et al, 2014;Reyazuddin et al, 2014;Rajasekaran et al, 2015). This may suggest that, in schizophrenia, there is an environment of oxidative stress, which would lead to the recruitment of the IP and 11S αβ RP in response to the increased oxidative load.…”

Section: Discussionmentioning

confidence: 99%

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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“…Several underlying mechanisms including neurotransmitter abnormality, immuno-inflammatory, oxidative and nitrosative stress (IO&NS) pathway, mitochondrial dysfunction, tryptophan catabolite (TRYCAT) pathway etc. contribute to neuroprogressive changes in schizophrenia Venkatasubramanian and Debnath 2013;Debnath and Berk 2014;Rajasekaran et al 2015). Amongst these, the IO&NS pathway has emerged as one of the predominant mechanisms of neuroprogression in schizophrenia .…”

Section: T-cell Network and Neuroprogression In Schizophreniamentioning

confidence: 99%

Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment

Debnath

2015

J Neuroimmune Pharmacol

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Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.

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Mitochondrial dysfunction in schizophrenia: Pathways, mechanisms and implications

Cited by 242 publications

References 186 publications

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment

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