Marked reduction of soluble superoxide dismutase-1 (SOD1) in cerebrospinal fluid of patients with recent-onset schizophrenia
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Molecular Psychiatry
(Impact Factor: 14.5).
02/2012; 18(1). DOI: 10.1038/mp.2012.6
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
Available from: Oliver Schubert
- "Another potential source of increased brain ROS is mitochondrial dysfunction (Leadsham et al., 2013), and several mitochondrial proteins were implicated in our findings (Table 1and 4), thus complementing previous evidence for mitochondrial changes in psychiatric disorders (Konradi et al., 2004;Clay et al., 2011). In our analyses, antioxidant enzymes such as superoxide dismutase 1 (SOD1), were found altered in hippocampal tissue (Focking et al., 2011a) (Table 1and 4) and were central to the top IPA protein networks in schizophrenia and bipolar disorder (Fig. 1 and 2), supporting previous findings (Coughlin et al., 2013;Brown et al., 2014;Emiliani et al., 2014). Increased brain levels of ROS lead to selective damage of fast-spiking GABAergic interneurons in rodent cortex (Behrens et al., 2007), and can directly regulate the strength of inhibitory GABAergic transmission at the postsynaptic site through GABA A receptor recruitment (Accardi et al., 2014). "
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ABSTRACT: Neuropathological changes of the hippocampus have been associated with psychotic disorders such as schizophrenia and bipolar disorder. Recent work has particularly implicated hippocampal GABAergic interneurons in the pathophysiology of these diseases. However, the molecular mechanisms underlying structural and cellular hippocampal pathology remain poorly understood. We used data from comprehensive difference-in-gel electrophoresis (2-D DIGE) investigations of postmortem human hippocampus of people with schizophrenia and bipolar disorder, covering the acidic (isoelectric point (pI) between pH4 and 7) and, separately, the basic (pI between pH6 and 11) sub-proteome, for Ingenuity Pathway Analysis (IPA) of implicated protein networks and pathways. Comparing disease and control cases, we identified 58 unique differentially expressed proteins in schizophrenia, and 70 differentially expressed proteins in bipolar disorder, using mass spectrometry. IPA implicated, most prominently, 14-3-3 and aryl hydrocarbon receptor signaling in schizophrenia, and gluconeogenesis/glycolysis in bipolar disorder. Both disorders were characterized by alterations of proteins involved in the oxidative stress response, mitochondrial function, and protein-endocytosis, -trafficking, -degradation, and -ubiquitination. These findings are interpreted with a focus on GABAergic interneuron pathology in the hippocampus.
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ABSTRACT: Abstract Health messages on low-energy diets for healthy weight loss are muddled and not working, and obesity rates are rising. Are there missing links? Accumulating evidence shows that humans have well developed 'self-addictive' appetite pathways to enhance the uptake of highly energy-dense food. Humans synthesize fewer co-factors and vitamins than other mammals and must ingest them. Both processes probably arose to maximize available energy for the developing, large association cortex of the human brain. The default phenotype resulting from consuming an 'addictive', westernized, highly refined, energy-dense, hypomicronutrient diet is 'malnutritive obesity' or 'malnubesity'. A relative lack of antioxidant (and other) co-factors contributes to inefficiently oxidized energy. This 'stress' leads to central fat deposition, disordered energy use by cell mitochondria, especially in muscle and liver, and malfunctioning immune, coagulation, endothelial, and other systems. The resultant problems appear to range from epigenetic reprogramming in utero to end organ damage of the metabolic syndrome and the immune failure of cancer. Treatment of 'malnubesity' may require: (1) understanding the drivers and mechanisms of addictions, (2) reprioritizing satiating, micronutrient-dense whole foods, (3) nonjudgmental general, psychological, and medical support for those at risk or affected by obesity; and (4) practical incentives/regulation for healthy food production and distribution.
Available from: Kazu Nakazawa
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Our previous studies indicated that N-methyl-D-aspartate receptor (NMDAR) deletion from a subset of corticolimbic interneurons in the mouse brain during early postnatal development is sufficient to trigger several behavioral and pathophysiological features resembling the symptoms of human schizophrenia. Interestingly, many of these behavioral phenotypes are exacerbated by social isolation stress. However, the mechanisms underlying the exacerbating effects of social isolation are unclear.
With γ-aminobutyric acid-ergic interneuron-specific NMDAR hypofunction mouse model (Ppp1r2-Cre/fGluN1 knockout [KO] mice), we investigated whether oxidative stress is implicated in the social isolation-induced exacerbation of schizophrenia-like phenotypes and further explored the underlying mechanism of elevated oxidative stress in KO mice.
The reactive oxygen species (ROS) level in the cortex of group-housed KO mice was normal at 8 weeks although increased at 16 weeks old. Postweaning social isolation (PWSI) augmented the ROS levels in KO mice at both ages, which was accompanied by the onset of behavioral phenotype. Chronic treatment with apocynin, an ROS scavenger, abolished markers of oxidative stress and partially alleviated schizophrenia-like behavioral phenotypes in KO mice. Markers of oxidative stress after PWSI were especially prominent in cortical parvalbumin (PV)-positive interneurons. The vulnerability of PV interneurons to oxidative stress was associated with downregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial energy metabolism and antioxidation.
These results suggest that a PWSI-mediated impairment in antioxidant defense mechanisms, presumably mediated by PGC-1α downregulation in the NMDAR-deleted PV-positive interneurons, results in oxidative stress, which, in turn, might contribute to exacerbation of schizophrenia-like behavioral phenotypes.
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