Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis - PubMed (original) (raw)

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

Edward J Goetzl et al. Transl Psychiatry. 2020.

Abstract

Potentially neurotoxic systems involved in traumatic and degenerative diseases of the brain were assessed in acute psychosis. Astrocyte-derived exosomes (ADEs) and neuron-derived exosomes (NDEs) were immunoprecipitated from plasma of ten untreated first-episode psychotics (FPs) and ten matched normal controls (Cs). Neural mitochondrial electron transport and complement proteins were extracted, quantified by ELISAs and normalized with levels of CD81 exosome marker. Levels of subunits 1 and 6 of NADH-ubiquinone oxidoreductase (complex I) and subunit 10 of cytochrome b-c1 oxidase (complex III), but not of subunit 1 of cytochrome C oxidase (complex IV) or superoxide dismutase 1 (SOD1) were significantly lower in ADEs and NDEs of FPs than Cs. This dysregulated pattern of electron transport proteins is associated with increased generation of reactive oxygen species. ADE glial fibrillary acidic protein levels were significantly higher in FPs than Cs, indicating a higher percentage of inflammatory astrocytes in FPs. ADE levels of C3b opsonin were significantly higher and those of C5b-9 attack complex was marginally higher in FPs than Cs. A significantly lower ADE level of the C3 convertase inhibitor CD55 may explain the higher levels of C3 convertase-generated C3b. ADE levels of the neuroprotective protein leukemia inhibitory factor (LIF) were significantly lower in FPs than Cs, whereas levels of IL-6 were no different. Plasma neural exosome levels of electron transport and complement proteins may be useful in predicting FP and guiding therapy. SOD mimetics, C3 convertase inhibitors and LIF receptor agonists also may have therapeutic benefits in FP.

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Conflict of interest statement

Dr. Goetzl has filed an application with the US Office of Patents and Trademarks for the exosome methodology used in this research, no other authors have any conflict of interests.

Figures

Fig. 1

Fig. 1. Protein constituents of the mitochondrial oxidative phosphorylation system in NDEs and ADEs.

Each point represents the value for one study participant. The mean ± S.E.M. of control (C) and first-episode psychosis (FP) groups, respectively, were 792 ± 68.2 pg/ml and 907 ± 80.4 pg/ml for NDEs and 846 ± 129 pg/ml and 1146 ± 141 pg/ml for ADEs for CD81 (a); 1437 ± 223 pg/ml and 912 ± 89.2 pg/ml for NDEs and 2010 ± 326 pg/ml and 1195 ± 161 pg/ml for ADEs for ND1 subunit of NADH-ubiquinone oxidoreductase (complex I) (b); 1574 ± 246 pg/ml and 542 ± 62.1 pg/ml for NDEs and 2363 ± 458 pg/ml and 825 ± 166 pg/ml for ADEs for ND6 subunit of NADH-ubiquinone oxidoreductase (complex I) (c); 1404 ± 112 pg/ml and 635 ± 53.8 pg/ml for NDEs and 1916 ± 315 pg/ml and 236 ± 47.2 pg/ml for ADEs for subunit 10 of cytochrome b-c1 (complex III) (d); 10975 ± 1461 pg/ml and 9750 ± 2011 pg/ml for NDEs and 14080 ± 2348 pg/ml and 9080 ± 1948 pg/ml for ADEs for subunit 1 of cytochrome c oxidase (complex IV) (e); and 2403 ± 672 pg/ml and 1829 ± 315 pg/ml for NDEs and 5472 ± 724 pg/ml and 4219 ± 723 pg/ml for ADEs for superoxide dismutase 1 (SOD1) (f). All values in B – F and in Fig. 2 were normalized for content of the exosome marker CD81. Statistical significance of differences in values between C and FP groups for NDEs and ADEs were calculated by two sample t tests; †, p < 0.05; *, p < 0.01; **, p < 0.001.

Fig. 2

Fig. 2. Complement and cytokine effector proteins in ADEs.

Each point represents the value for one study participant. The mean ± S.E.M. of control (C) and first-episode psychosis (FP) groups, respectively, were 111,641 ± 14,822 pg/ml and 466,335 ± 100,239 pg/ml for GFAP (a); 10,167 ± 994 pg/ml and 117,468 ± 26,305 pg/ml for C3b (b); 330 ± 56.0 pg/ml and 573 ± 100 pg/ml for C5b-9 (c); 49,621 ± 6073 pg/ml and 7652 ± 1452 pg/ml for CD55 (DAF) (d); 1087 ± 299 pg/ml and 613 ± 134 pg/ml for CD59 (e); 44.8 ± 5.35 pg/ml and 45.0 ± 5.85 pg/ml for IL-6 (f); and 1519 + 204 pg/ml and 424 + 64.2 pg/ml for LIF (g). Statistical significance of differences in values between C and FP groups were calculated by two sample t tests; †, p < 0.05; *, p < 0.01; **, p < 0.001.

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