Altered proteins of the anterior cingulate cortex white matter proteome in schizophrenia

Alterations in the circuitry between and within different brain regions including the anterior cingulate cortex (ACC) is implicated in the neuropathology of schizophrenia. The involvement of white matter in schizophrenia is becoming increasingly apparent with reports of structural, morphological and genetic alterations occurring in the disease. The 2‐DE was employed to reveal significantly altered proteins within the ACC white matter proteome in a schizophrenia cohort (n = 10) relative to controls (n = 10). From the 423 matched spots between the two groups, the levels of 32 protein spots were altered in the schizophrenia ACC white matter. Of these, 30 spots were identified using MS. The majority of the altered proteins in schizophrenia function in metabolism, the cytoskeleton, and the synapse. These proteomic data suggest that the brain circuitry involving the ACC white matter tracts is altered in schizophrenia, possibly caused by depleted glucose metabolism and altered structural components of this region.

[1]  N. Andreasen,et al.  Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients , 1997, The Lancet.

[2]  Andrew L. Lemire,et al.  Deficient Hippocampal Neuron Expression of Proteasome, Ubiquitin, and Mitochondrial Genes in Multiple Schizophrenia Cohorts , 2005, Biological Psychiatry.

[3]  F. Benes,et al.  Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood. , 1994, Archives of general psychiatry.

[4]  F. Benes,et al.  The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects , 2001, Biological Psychiatry.

[5]  J. Julien,et al.  Delayed Maturation of Regenerating Myelinated Axons in Mice Lacking Neurofilaments , 1997, Experimental Neurology.

[6]  K. Blennow,et al.  Comparative proteome analysis of thalamus in MK‐801‐treated rats , 2004, Proteomics.

[7]  J. Sweeney,et al.  Decreased caudate volume in neuroleptic-naive psychotic patients. , 1998, The American journal of psychiatry.

[8]  R. Yolken,et al.  Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress , 2004, Molecular Psychiatry.

[9]  Sabine Landau,et al.  Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. , 2002, Cerebral cortex.

[10]  E. G. Jones,et al.  Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients. , 1996, Archives of general psychiatry.

[11]  C. Beasley,et al.  The density and spatial distribution of gabaergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia , 2002, Biological Psychiatry.

[12]  C. Harper,et al.  Differential protein expression in the prefrontal white matter of human alcoholics: a proteomics study , 2006, Molecular Psychiatry.

[13]  Manzar Ashtari,et al.  White matter abnormalities in early-onset schizophrenia: a voxel-based diffusion tensor imaging study. , 2005, Journal of the American Academy of Child and Adolescent Psychiatry.

[14]  W. Honer,et al.  Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins , 2003, Molecular Psychiatry.

[15]  K. Davis,et al.  Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia. , 1997, Archives of general psychiatry.

[16]  S. Cordwell,et al.  A proteome analysis of the anterior cingulate cortex gray matter in schizophrenia , 2006, Molecular Psychiatry.

[17]  D. Weinberger,et al.  From neuropathology to neurodevelopment , 1995, The Lancet.

[18]  Sabine Bahn,et al.  Gene expression in bipolar disorder and schizophrenia: new approaches to old problems. , 2002, Bipolar disorders.

[19]  M. Iyo,et al.  Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET , 1997, Nature.

[20]  W T Carpenter,et al.  Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome. , 1992, Archives of general psychiatry.

[21]  B. Vogt,et al.  Human cingulate cortex: Surface features, flat maps, and cytoarchitecture , 1995, The Journal of comparative neurology.

[22]  Yalin Wang,et al.  Hydrogen Peroxide Inhibits the Vacuolar H+‐ATPase in Brain Synaptic Vesicles at Micromolar Concentrations , 1998, Journal of neurochemistry.

[23]  Eve C. Johnstone,et al.  White Matter Density in Patients with Schizophrenia, Bipolar Disorder and Their Unaffected Relatives , 2005, Biological Psychiatry.

[24]  T M Hyde,et al.  Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. , 1992, Archives of neurology.

[25]  R. Yolken,et al.  Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder , 2000, Molecular Psychiatry.

[26]  J. Meador-Woodruff,et al.  Molecular Abnormalities of the Glutamate Synapse in the Thalamus in Schizophrenia , 2003, Annals of the New York Academy of Sciences.

[27]  L. Wilkinson,et al.  Behavioural, histochemical and biochemical consequences of selective immunolesions in discrete regions of the basal forebrain cholinergic system , 1994, Neuroscience.

[28]  R. Scheller,et al.  Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. , 1992, Science.

[29]  M. M. Bradford A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[30]  A. Graybiel,et al.  Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia , 1999, Neuroscience.

[31]  Dagmar Galter,et al.  ALDH1 mRNA: presence in human dopamine neurons and decreases in substantia nigra in Parkinson's disease and in the ventral tegmental area in schizophrenia , 2003, Neurobiology of Disease.

[32]  T. Kinoshita,et al.  Reduced White Matter Volume of the Caudate Nucleus in Patients with Schizophrenia , 2004, Neuropsychobiology.

[33]  Paul J. Harrison,et al.  Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis , 2003, Molecular Psychiatry.

[34]  M. Casanova,et al.  Decreased DOPAC in the anterior cingulate cortex of individuals with schizophrenia , 1995, Biological Psychiatry.

[35]  J. Sangiovanni,et al.  Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[36]  T. MacRae Tubulin post-translational modifications--enzymes and their mechanisms of action. , 1997, European journal of biochemistry.

[37]  E. Nogales Structural insights into microtubule function. , 2000, Annual review of biochemistry.

[38]  Vincent Magnotta,et al.  Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. , 2003, Archives of general psychiatry.

[39]  R. Tandon,et al.  Positive and negative syndromes in schizophrenia. , 1989, The American journal of psychiatry.

[40]  I. Silver,et al.  Metabolism and role of glutamate in mammalian brain , 1990, Progress in Neurobiology.

[41]  M. Tsuang Schizophrenia: genes and environment , 2000, Biological Psychiatry.

[42]  F. Benes Alterations of neural circuitry within layer II of anterior cingulate cortex in schizophrenia. , 1999, Journal of psychiatric research.

[43]  Philip D. Harvey,et al.  White matter changes in schizophrenia: evidence for myelin-related dysfunction. , 2003, Archives of general psychiatry.

[44]  R. Little,et al.  Partial Purification and Properties of Human Brain Aldehyde Dehydrogenases , 1985, Journal of neurochemistry.

[45]  Patrick R. Hof,et al.  Molecular and Cellular Evidence for an Oligodendrocyte Abnormality in Schizophrenia , 2002, Neurochemical Research.

[46]  Angus M. Brown,et al.  Astrocyte glycogen metabolism is required for neural activity during aglycemia or intense stimulation in mouse white matter , 2005, Journal of neuroscience research.

[47]  C. Karson,et al.  Decreased mesopontine choline acetyltransferase levels in schizophrenia. Correlations with cognitive functions. , 1996, Molecular and chemical neuropathology.

[48]  Andrei G. Vlassenko,et al.  Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain. , 2004, Proceedings of the National Academy of Sciences of the United States of America.