Sp1 Expression Is Disrupted in Schizophrenia; A Possible Mechanism for the Abnormal Expression of Mitochondrial Complex I Genes, NDUFV1 and NDUFV2

The prevailing hypothesis regards schizophrenia as a polygenic disease, in which multiple genes combine with each other and with environmental stimuli to produce the variance of its clinical symptoms. We investigated whether the ubiquitous transcription factor Sp1 is abnormally expressed in schizophrenia, and consequently can affect the expression of genes implicated in this disorder. promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin.These findings suggest that abnormality in Sp1, which can be the main activator/repressor or act in combination with additional transcription factors and is subjected to environmental stimuli, can contribute to the polygenic and clinically heterogeneous nature of schizophrenia

Neuroanatomical Pattern of Mitochondrial Complex I Pathology Varies between Schizophrenia, Bipolar Disorder and Major Depression

BACKGROUND:Mitochondrial dysfunction was reported in schizophrenia, bipolar disorderand major depression. The present study investigated whether mitochondrial complex I abnormalities show disease-specific characteristics. METHODOLOGY/PRINCIPAL FINDINGS:mRNA and protein levels of complex I subunits NDUFV1, NDUFV2 and NADUFS1, were assessed in striatal and lateral cerebellar hemisphere postmortem specimens and analyzed together with our previous data from prefrontal and parieto-occipital cortices specimens of patients with schizophrenia, bipolar disorder, major depression and healthy subjects. A disease-specific anatomical pattern in complex I subunits alterations was found. Schizophrenia-specific reductions were observed in the prefrontal cortex and in the striatum. The depressed group showed consistent reductions in all three subunits in the cerebellum. The bipolar group, however, showed increased expression in the parieto-occipital cortex, similar to those observed in schizophrenia, and reductions in the cerebellum, yet less consistent than the depressed group. CONCLUSIONS/SIGNIFICANCE:These results suggest that the neuroanatomical pattern of complex I pathology parallels the diversity and similarities in clinical symptoms of these mental disorders

Primer sequences and PCR conditions.

<p>All templates were initially denatured for 5 min at 94°C, and after completing all cycles, were extended a final extension of 10 min at 72°C.</p

Cerebellar lateral hemisphere mRNA expression of complex I subunits.

<p>mRNA levels of NDUFV1, NDUFV2 and NDUFS1 subunits of complex I in post mortem cerebellar lateral hemisphere of patients with schizophrenia (SCH, n = 15), major depression (MD, n = 15) and bipolar disorder (BP, n = 15), and of normal controls (n = 15). Statistical significant differences vs. the control group were observed in all three subunits in the major depression group and in the NDUFV1 in the bipolar group. No statistically significant difference was observed in the schizophrenic group.</p

Cerebellar lateral hemisphere protein expression of complex I subunits.

<p>Protein levels of the 51-, 24-and 75-kDa subunits of complex I in post mortem Cerebellar lateral hemisphere of patients with schizophrenia (SCH, n = 15), major depression (MD, n = 15) and bipolar disorder (BP, n = 15), and of normal controls (n = 15). Statistical significant differences vs. the control group were observed in all three subunits in the major depression group and in the 51-kDa and the 75-kDa subunits in the bipolar group. No statistically significant difference was observed in the schizophrenic group.</p

The effect of mithramycin on the transcriptional activity of the <i>NDUFV2</i> predicted promoter in SH-SY5Y cells.

<p>A. Cells were transiently transfected with two concentrations of the p<i>NDUFV2</i>-Luc reporter construct (construct) for 24 hrs and analyzed for luciferase activity. B. One hour before the transfection cells were pre-incubated with or without mithramycin (150 nM). The results are means±SD of three experiments normalized for10⁶ cells. *p<0.0001.</p

Demographic data for post mortem brains.

a<p>Lifetime antipsychotic dose in fluphenazine milligram equivalents. N/A–not applicable</p

Protein levels of <i>NDUFV1, NDUFV2</i> and <i>NDUFS1</i> subunits of complex I, but not that of Sp1 are reduced following treatment of SH-SY5Y cells with mithramycin.

<p>Densitometry value of protein levels (A) and a representative gel (B) of all 4 genes in cells treated for 24 hrs with 150 nM mithramycin. Results are means±SD of 3–4 experiments. *p<0.005 **p<0.014 ***p<0.024 vs. untreated control cells.</p

Protein levels of 51-, 24-and 75-kDa subunits of complex I in post mortem striatum including the nucleus accumbens of patients with schizophrenia (SCH, n = 15), major depression (MD, n = 15) and bipolar disorder (BP, n = 15) and of normal controls (n = 15).

<p>Statistical significant differences vs. the control group were observed in the 51- and 24-kDa subunits of the schizophrenic group and in the 75-kDa subunit of the bipolar group. No statistically significant difference was observed in the depressed group.</p