Alfredo Ramos-Miguel1, Clare L Beasley1, Andrew J Dwork2, J John Mann2, Gorazd Rosoklija2, Alasdair M Barr3, William G Honer4. 1. BC Mental Health & Addictions Research Institute, University of British Columbia, Vancouver, BC, Canada; Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. 2. Department of Psychiatry, Columbia University, New York, New York. 3. BC Mental Health & Addictions Research Institute, University of British Columbia, Vancouver, BC, Canada; Department of Pharmacology, University of British Columbia, Vancouver, BC, Canada. 4. BC Mental Health & Addictions Research Institute, University of British Columbia, Vancouver, BC, Canada; Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. Electronic address: william.honer@ubc.ca.
Abstract
BACKGROUND: Synaptic dysfunction in schizophrenia may be associated with abnormal expression or function of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin, synaptosomal-associated protein 25 [SNAP25], vesicle-associated membrane protein [VAMP]) forming the molecular complex underlying neurosecretion. The impact of such abnormalities on efficient SNARE heterotrimer formation is poorly understood. We investigated putative SNARE dysfunction, along with possible roles for the SNARE binding partners Munc18-1, complexins (Cplx) 1/2, and synaptotagmin in brains from autopsies of individuals with and without schizophrenia. METHODS: Postmortem samples were obtained from orbitofrontal cortex (OFC) and/or anterior cingulate cortex from two separate cohorts (n = 15 + 15 schizophrenia cases, n = 13 + 15 control subjects). SNARE interactions were studied by immunoprecipitation and one- or two-dimensional blue native polyacrylamide gel electrophoresis (BN-PAGE). RESULTS: In the first cohort, syntaxin, Munc18-1, and Cplx1, but not VAMP, Cplx2, or synaptotagmin, were twofold enriched in SNAP25 immunoprecipitated products from schizophrenia OFC in the absence of any alterations in total tissue homogenate levels of these proteins. In BN-PAGE, the SNARE heterotrimer was identified as a 150-kDa complex, increased in schizophrenia samples from cohort 1 (OFC: +45%; anterior cingulate cortex: +44%) and cohort 2 (OFC: +40%), with lower 70-kDa SNAP25-VAMP dimer (-37%) in the OFC. Upregulated 200-kDa SNARE-Cplx1 (+65%) and downregulated 550-kDa Cplx1-containing oligomers (-24%) in schizophrenia OFC were identified by BN-PAGE. These findings were not explained by postmortem interval, antipsychotic medication, or other potentially confounding variables. CONCLUSIONS: The findings support the hypothesis of upregulated SNARE complex formation in schizophrenia OFC, possibly favored by enhanced affinity for Munc18-1 and/or Cplx1. These alterations offer new therapeutic targets for schizophrenia.
BACKGROUND: Synaptic dysfunction in schizophrenia may be associated with abnormal expression or function of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin, synaptosomal-associated protein 25 [SNAP25], vesicle-associated membrane protein [VAMP]) forming the molecular complex underlying neurosecretion. The impact of such abnormalities on efficient SNARE heterotrimer formation is poorly understood. We investigated putative SNARE dysfunction, along with possible roles for the SNARE binding partners Munc18-1, complexins (Cplx) 1/2, and synaptotagmin in brains from autopsies of individuals with and without schizophrenia. METHODS: Postmortem samples were obtained from orbitofrontal cortex (OFC) and/or anterior cingulate cortex from two separate cohorts (n = 15 + 15 schizophrenia cases, n = 13 + 15 control subjects). SNARE interactions were studied by immunoprecipitation and one- or two-dimensional blue native polyacrylamide gel electrophoresis (BN-PAGE). RESULTS: In the first cohort, syntaxin, Munc18-1, and Cplx1, but not VAMP, Cplx2, or synaptotagmin, were twofold enriched in SNAP25 immunoprecipitated products from schizophrenia OFC in the absence of any alterations in total tissue homogenate levels of these proteins. In BN-PAGE, the SNARE heterotrimer was identified as a 150-kDa complex, increased in schizophrenia samples from cohort 1 (OFC: +45%; anterior cingulate cortex: +44%) and cohort 2 (OFC: +40%), with lower 70-kDa SNAP25-VAMP dimer (-37%) in the OFC. Upregulated 200-kDa SNARE-Cplx1 (+65%) and downregulated 550-kDa Cplx1-containing oligomers (-24%) in schizophrenia OFC were identified by BN-PAGE. These findings were not explained by postmortem interval, antipsychotic medication, or other potentially confounding variables. CONCLUSIONS: The findings support the hypothesis of upregulated SNARE complex formation in schizophrenia OFC, possibly favored by enhanced affinity for Munc18-1 and/or Cplx1. These alterations offer new therapeutic targets for schizophrenia.
Authors: Clare L Beasley; William G Honer; Klaus Bergmann; Peter Falkai; Dieter Lütjohann; Thomas A Bayer Journal: Bipolar Disord Date: 2005-10 Impact factor: 6.744
Authors: Patricia A Boyle; Robert S Wilson; Lei Yu; Alasdair M Barr; William G Honer; Julie A Schneider; David A Bennett Journal: Ann Neurol Date: 2013-07-10 Impact factor: 10.422
Authors: Ken Sawada; Alasdair M Barr; Masato Nakamura; Kunimasa Arima; Clint E Young; Andrew J Dwork; Peter Falkai; Anthony G Phillips; William G Honer Journal: Arch Gen Psychiatry Date: 2005-03
Authors: Alexander F Jeans; Peter L Oliver; Reuben Johnson; Marco Capogna; Jenny Vikman; Zoltán Molnár; Arran Babbs; Christopher J Partridge; Albert Salehi; Martin Bengtsson; Lena Eliasson; Patrik Rorsman; Kay E Davies Journal: Proc Natl Acad Sci U S A Date: 2007-02-05 Impact factor: 11.205
Authors: Peter M Thompson; Dianne A Cruz; Elizabeth A Fucich; Dianna Y Olukotun; Masami Takahashi; Makoto Itakura Journal: Mol Neuropsychiatry Date: 2015-12-01
Authors: Alfredo Ramos-Miguel; Andrea A Jones; Ken Sawada; Alasdair M Barr; Thomas A Bayer; Peter Falkai; Sue E Leurgans; Julie A Schneider; David A Bennett; William G Honer Journal: Neurobiol Dis Date: 2018-02-26 Impact factor: 5.996
Authors: Vilte E Barakauskas; Annie Moradian; Alasdair M Barr; Clare L Beasley; Gorazd Rosoklija; J John Mann; Boro Ilievski; Aleksandar Stankov; Andrew J Dwork; Peter Falkai; Gregg B Morin; William G Honer Journal: Schizophr Res Date: 2016-03-09 Impact factor: 4.939
Authors: Alfredo Ramos-Miguel; Christa Hercher; Clare L Beasley; Alasdair M Barr; Thomas A Bayer; Peter Falkai; Sue E Leurgans; Julie A Schneider; David A Bennett; William G Honer Journal: Mol Neurodegener Date: 2015-12-02 Impact factor: 14.195