• Alfredo Ramos-Miguel, Vilte Barakauskas, Jehan Alamri, Masatoshi Miyauchi, Alasdair M Barr, Clare L Beasley, Gorazd Rosoklija, J John Mann, Andrew J Dwork, Annie Moradian, Gregg B Morin, and William G Honer.
• BC Mental Health and Addictions Research Institute, 938 West 28th Ave, Vancouver, BC V5Z 4H4, Canada; Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada; Department of Pharmacology, University of the Basque Country, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Barrio Sarriena, s/n, 48940 Leioa, Biscay, Spain.
• Neuroscience. 2019 Nov 10; 420: 97-111.

AbstractAbnormalities of SNAP25 (synaptosome-associated protein 25) amount and protein-protein interactions occur in schizophrenia, and may contribute to abnormalities of neurotransmitter release in patients. However, presynaptic terminal function depends on multiple subcellular mechanisms, including energy provided by mitochondria. To explore the SNAP25 interactome in schizophrenia, we immunoprecipitated SNAP25 along with interacting proteins from the ventromedial caudate of 15 cases of schizophrenia and 13 controls. Proteins were identified with mass spectrometry-based proteomics. As well as 15 SNARE- (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) associated proteins, we identified 17 mitochondria-associated and four other proteins. The mitochondrial small GTPase ARF1 (ADP-ribosylation factor 1) was identified in eight schizophrenia SNAP25 immunoprecipitates and none from controls (P = 0.004). Although the ARF1-SNAP25 interaction may be increased, immunoblotting demonstrated 21% lower ARF1-21 (21 kiloDaltons) in schizophrenia samples (P = 0.04). In contrast, the mitochondrial protein UQCRC1 (ubiquinol-cytochrome c reductase core protein 1) did not differ. Lower ARF1-21 levels were associated with the previously reported increased SNAP25-syntaxin interaction in schizophrenia (r = -0.39, P = 0.04). Additional immunoprecipitation studies confirmed the ARF1-21-SNAP25 interaction, independent of UQCRC1. Both ARF1 and SNAP25 were localized to synaptosomes. Confocal microscopy demonstrated co-localization of ARF1 and SNAP25, and further suggested fivefold enrichment of ARF1 in synaptosomes containing an excitatory marker (vesicular glutamate transporter) compared with synaptosomes containing an inhibitory marker (vesicular GABA transporter). The present findings suggest an association between abnormalities of SNARE proteins involved with vesicular neurotransmission and the mitochondrial protein ARF1 that may contribute to the pathophysiology of schizophrenia.Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

19 keywords...

hide…