Bernhard Bogerts

Diana Dürrschmidt

Gerburg Keilhoff

Hans-Gert Bernstein

Henrik Dobrowolny

Johann Steiner

Karl-Heinz Smalla

Michael R Kreutz

English

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Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010 39Diana Dürrschmidt et al. Increased oligodendroglial expression INCREASED OLIGODENDROGLIAL EXPRESSION OF THE CELL PROLIFERATIONCONTROLLING PROTEIN PROHIBITIN IN SCHIZOPHRENIA.A HINT FOR CELL CYCLE ABNORMALITIES?Diana Dürrschmidt1, Karl-Heinz Smalla2, Michael R. Kreutz2, Henrik Dobrowolny1, Johann Steiner1, Gerburg Keilhoff  3, Bernhard Bogerts1, Hans-Gert Bernstein11Department of Psychiatry, University of Magdeburg, Leipziger St. 44, D-39120 Magdeburg2 Institute for Neurobiology, D-39118 Magdeburg3Institute of Biochemistry and Cell Biology, University of Magdeburg, D-39120 Magdeburg, GermanyAbstract Oligodendrocytes (OLs) are in many ways im-plicated in the pathophysiology of schizophrenia. However, very little is currently known about possible OL cell cycle disturbances in schizophrenia, a phe-nomenon which has been described for the birth of new hippocampal neurons in schizophrenics. When morphometrically analyzing the density of prohibitin-expressing OLs in diff erent prefrontal white matter areas of patients with schizophrenia, we found a sig-nifi cantly increased density of this OL subpopulation in the anterior cingulate cortex. Prohibitin is a mito-chondrial protein, which is expressed both in neurons and OLs. Among many other functions, this protein plays an important role in the control of cell prolifera-tion and apoptosis by regulating the GTPase OPA1. Hence, out data might be taken as possible hint for disease-related cell cycle abnormalities. IntroductionTo the key fi ndings in the neuropathology of schizophrenia belong decreases in OL density as well an altered spatial distribution, deviant cell morphol-ogy and protein expression patterns of these cells, which manifest themselves in an impaired chemical composition of myelin, abberant communication be-tween diff erent brain regions and other white matter abnormalities (reviewed in refs. 1 and 2). Th e reasons for reduced OL number and myelin-specifi c gene ex-pression impariments in schizophrenia are yet poorly understood. When analysing what signalling path-ways may elicit these defi cits, Katsel et al.1 found that especially genes associated with canonical cell cycle pathways were aff ected in the anterior cingulate gyrus (ACG), the region exhibiting the most profound my-elin-specifi c gene expression changes in schizophre-nia. Th us, while almost all other studies have focused on seeking abnormalities that impede OL maturation at the level of migration, myelination, and survival1,2, the results of Katsel ś group3. provide the fi rst experi-mental evidence that not only neurons, but also OLs (or, more precisely, OL progenitor cells), may suff er from cell cycle disturbances in schizophrenia. Our group has recently shown that the neuronal expression of prohibitin is upregulated in schizophre-nia, which might be an indication of disease-related synaptic pathology4. Subsequent analysis revealed that the protein is also abundantly expressed in white mat-ter OLs5. Emerging evidence in favour of a prominent role of prohibitin in the control of cell cycle (ref. 6 and others) encouraged us to analyse the OL expression of prohibitin in diff erent brain white matter areas pa-tients with schizophrenia.Diana Dürrschmidt et al. Increased oligodendroglial expression 40 Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010Material and methodsAll brains were obtained from Magdeburg brain bank. Brains of six individuals with clinically con-fi rmed schizophrenia and seven matched controls without neurological or psychiatric disorders were studied.  Th e tissue preparation was as described ear-lier7. Prohibitin immunoreactivity was detected with a monoclonal antibody using the nickel-enhanced avdin-biotin technique4. Prohibitin is present in mul-tiple mature OLs as well as in progenitor cells located in the subventricular zone. Th e density of prohibitin-expressing OLs was determined in left and right dor-solateral prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex as recently described8. ResultsQualitatively, probibitin was found to be ex-pressed in a majority of white matter OLs and some gray matter OLs. Th e intracellular immunostaining was confi ned to granule-like organelles, which were distributed within the cytoplasm and are most prob-ably mitochondria. Prohibitin-immunoreactive cells were also observed in the subventricular zone. Mor-phometrically, a signifi cant (p=0.035) increase in the numerical density of prohibitin immunoreactive OLs was found in the right dorsolateral prefrontal cortex. In all other brain areas under study no diff erences be-tween schizophrenics and controls were seen. A limi-tation of this study is the small number of cases.DiscussionAlthough a nuclear localization of prohibitin has also been reported, there is yet consensus that this protein is predominantly localized to the mitochon-dria, where it might have roles in the maintenance of mitochondrial morphology and  function, protection against senescence, tumor suppression, apoptosis and the regulation of cell-cycle progression6,9. Previously, the latter function was seriously questioned, because it is hard to imagine how a mitochondrial protein might manage this. A recent paper has convincingly shown that mitochondria-located prohibitin is indeed capable of controlling cell cycle by coupling cell pro-liferation to mitochondrial morphogenesis through the GTPase OPA16. Th us, the observed increased expression of the anti-proliferative protein prohibitin in dorsolateral prefrontal OLs might well be part of a disturbed signalling cascade which fi nally leads to an Ol impaired cell cycle activity in schizophrenia3. However, since prohibitin  is involved in a plethora of diff erent regulatory mechanisms, our data cannot be taken as an evidence for this, and further studies are clearly needed to learn more about  OL cell cycle abnormalities in schizophrenia. Th erefore, studies are in progress to co-stain prohibitin with the prolifera-tion marker Ki67.References1 URANOVA NA, VOSTRIKOV VM, VIKHREVA OV, ZIMINA IS, KOLOMEETS NS, ORLOVSKAYA DD. Th e role of oligodendrocyte pathology in schizophrenia. Int J Neuropsychopharmacol. 2007; 10:537-545. 2. BERNSTEIN HG, STEINER J, BOGERTS B. Glial cells in schizophrenia: pathophysiological signifi cance and pos-sible consequences for therapy. Expert Rev Neurother. 2009; 9:1059-1071.3. KATSEL P, DAVIS KL, LI C, TAN W, GREENSTEIN E, KLEINER HOFFMAN LB, HAROUTUIAN V. Abnor-mal indices of cell cycle activity in schizphrenia in association with oligodendrocytes. Neuropsychopharmacology 2008; 33: 2993-3009.4. SMALLA KH, MIKHAYLOVA M, SAHIN J, BERNSTEIN HG, BOGERTS B, SCHMITT A, VAN DER SCHORS R, SMIT AB, LI KW, GUNDELFINGER ED, KREUTZ MR. A comparison of the synaptic proteome in human chronic schizophrenia and rat ketamine psychosis suggest that prohibitin is involved in the synaptic pathology of schizophrenia. Mol Psychiatry. 2008; 13:878-896.5. BERNSTEIN HG, SMALLA KH, MIKHAYLOVA M, SALIN J, BOGERTS B, SCHMITT A, VAN DER SCHORS R, SMIT G, LI KW, DÜRSCHMITT D, GUNDELFINGER ED. Emerging roles of prohibitin in schizo-phrenia: Evidence from human postmortem studies and rat model of psychosis. Eur Arch Psychiatry Clin Neurosci 2009; 259 (Suppl1): S99.6. MERKWIRTH C, DARGAZANLI S, TATSUTA T, GEIMER S, LÖWER B, WUNDERLICH FT, VON KLEISTRETZOW JC, WESTERMANN B, LANGER T. Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mito-cheondria. Genes Dev. 2008; 22, 476-488.7. BERNSTEIN HG, STANARIUS A, BAUMANN B, HENNING H, KRELL D, DANOS P, FALKAI P, BOGERTS B. 1998. Nitric oxide synthase-containing neurons in the human hypothalamus: Reduced number of immuno-reactive cells in the paraventricular nucleus of depressive pa-tients and schizophrenics. Neuroscience 1998; 83: 967-875.Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010 41Diana Dürrschmidt et al. Increased oligodendroglial expression 8. FARKAS N, LENDECKEL U, DOBROWOLNY H, FUNKE S, STEINER J , KEILHOFF G, SCHMITT A, BOGERTS B, BERNSTEIN HG. Reduced density of ADAM 12-immunoreactive oligodendrocytes in the anterior cingulate white matter of patients with schizophrenia. World J Biol Psychiatry in press.9. MISHRA S, MURPHY LC, NYOMBA BL, MURPHY LJ. Prohibitin: a potential target for new

Increased Oligodendroglial Expression of the Cell Proliferation-Controlling Protein Prohibitin in Schizophrenia. A Hint for Cell Cycle Abnormalities?

Increased Oligodendroglial Expression of the Cell Proliferation-Controlling Protein Prohibitin in Schizophrenia. A Hint for Cell Cycle Abnormalities?

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